Aryl sulfonamides

ABSTRACT

Compounds are provided that act as potent antagonists of the CCR9 receptor, and which have been further confirmed in animal testing for inflammation, one of the hallmark disease states for CCR9. The compounds are generally aryl sulfonamide derivatives and are useful in pharmaceutical compositions, methods for the treatment of CCR9-mediated diseases, and as controls in assays for the identification of CCR9 antagonists.

RELATED APPLICATIONS

This application claims priority to U.S. provisional application Ser.No. 60/427,670 filed Nov. 18, 2002. The disclosure of the priorityapplication is incorporated by reference herein in its entirety.

BACKGROUND OF THE INVENTION

The present invention provides compounds, pharmaceutical compositionscontaining one or more of those compounds or their pharmaceuticallyacceptable salts, which are effective in inhibiting the binding orfunction of various chemokines, such TECK, to the CCR9 receptor. Asantagonists or modulators for the CCR9 receptor, the compounds andcompositions have utility in treating inflammatory and immune disorderconditions and diseases.

Chemokines are chemotactic cytokines that are released by a wide varietyof cells and attract various types of immune system cells, such asmacrophages, T cells, eosinophils, basophils and neutrophils, to sitesof inflammation (reviewed in Schall, Cytokine, 3:165-183 (1991), Schall,et al., Curr. Opin. Immunol., 6:865 873 (1994) and Murphy, Rev. Immun.,12:593-633 (1994)). In addition to stimulating chemotaxis, other changescan be selectively induced by chemokines in responsive cells, includingchanges in cell shape, transient rises in the concentration ofintracellular free calcium ions ([Ca²⁺]), granule exocytosis, integrinup-regulation, formation of bioactive lipids (e.g., leukotrienes) andrespiratory burst, associated with leukocyte activation. Thus, thechemokines are early triggers of the inflammatory response, causinginflammatory mediator release, chemotaxis and extravasation to sites ofinfection or inflammation.

T lymphocyte (T cell) infiltration into the small intestine and colonhas been linked to the pathogenesis of Coeliac diseases, food allergies,rheumatoid arthritis, human inflammatory bowel diseases (IBD) whichinclude Crohn's disease and ulcerative colitis. Blocking trafficking ofrelevant T cell populations to the intestine can lead to an effectiveapproach to treat human IBD. More recently, chemokine receptor 9 (CCR9)has been noted to be expressed on gut-homing T cells in peripheralblood, elevated in patients with small bowel inflammation such asCrohn's disease and celiac disease. The only CCR9 ligand identified todate, TECK (thymus-expressed chemokine) is expressed in the smallintestine and the ligand receptor pair is now thought to play a pivotalrole in the development of IBD. In particular, this pair mediates themigration of disease causing T cells to the intestine. See for example,Zaballos, et al., J. Immunol., 162(10):5671-5675 (1999); Kunkel, et al.,J. Exp. Med. 192(5):761-768 (2000); Papadakis, et al., J. Immunol.,165(9):5069-5076 (2000); Papadakis, et al., Gastroenterology,121(2):246-254 (2001); Campbell, et al., J. Exp. Med., 195(1):135-141(2002); Wurbel, et al., Blood, 98(9):2626-2632 (2001); and Uehara, etal., J. Immunol, 168(6):2811-2819 (2002).

The identification of compounds that modulate the function of CCR9represents an attractive new family of therapeutic agents for thetreatment of inflammatory and other conditions and diseases associatedwith CCR9 activation, such as inflammatory bowel disease.

BRIEF SUMMARY OF THE INVENTION

The present invention is directed to compounds and pharmaceuticallyacceptable salts thereof, compositions, and methods useful in modulatingCCR9 chemokine activity. The compounds and salts thereof, compositions,and methods described herein are useful in treating or preventingCCR9-mediated conditions or diseases, including certain inflammatory andimmunoregulatory disorders and diseases.

In one embodiment, the inventive compounds are of the formula (I):

where X, Y and Z are as defined below. Salts of these compounds are alsowithin the scope of the invention.

In another aspect, the present invention provides compositions useful inmodulating CCR9 chemokine activity. In one embodiment, a compositionaccording to the present invention comprises a compound according to theinvention and a pharmaceutically acceptable carrier or excipient.

In yet another aspect, the present invention provides a method ofmodulating CCR9 function in a cell, comprising contacting the cell witha therapeutically effective amount of a compound or compositionaccording to the invention.

In still another aspect, the present invention provides a method formodulating CCR9 function, comprising contacting a CCR9 protein with atherapeutically effective amount of a compound or composition accordingto the invention.

In still another aspect, the present invention provides a method fortreating a CCR9-mediated condition or disease, comprising administeringto a subject a safe and effective amount of a compound or compositionaccording to the invention.

In addition to the compounds provided herein, the present inventionfurther provides pharmaceutical compositions containing one or more ofthese compounds, as well as methods for the use of these compounds intherapeutic methods, primarily to treat diseases associated with CCR9signaling activity.

BRIEF DESCRIPTION OF THE FIGURE

FIG. 1 is a graph showing in vivo efficacy for the CCR9 antagonisttested in Example 119. Closed triangle: vehicle; Open circle: CCR9antagonist of the formula:

DETAILED DESCRIPTION OF THE INVENTION General

The present invention is directed to compounds and salts thereof,compositions and methods useful in the modulation of chemokine receptorfunction, particularly CCR9 function. Modulation of chemokine receptoractivity, as used herein in its various forms, is intended to encompassantagonism, agonism, partial antagonism, inverse agonism and/or partialagonism of the activity associated with a particular chemokine receptor,preferably the CCR9 receptor. Accordingly, the compounds of the presentinvention are compounds which modulate at least one function orcharacteristic of mammalian CCR9, for example, a human CCR9 protein. Theability of a compound to modulate the function of CCR9, can bedemonstrated in a binding assay (e.g., ligand binding or agonistbinding), a migration assay, a signaling assay (e.g., activation of amammalian G protein, induction of rapid and transient increase in theconcentration of cytosolic free calcium), and/or cellular response assay(e.g., stimulation of chemotaxis, exocytosis or inflammatory mediatorrelease by leukocytes).

ABBREVIATIONS AND DEFINITIONS

When describing the compounds, compositions, methods and processes ofthis invention, the following terms have the following meanings, unlessotherwise indicated.

When describing the compounds, compositions, methods and processes ofthis invention, the following terms have the following meanings, unlessotherwise indicated.

“Alkyl” by itself or as part of another substituent refers to ahydrocarbon group which may be linear, cyclic, or branched or acombination thereof having the number of carbon atoms designated (i.e.,C₁₋₈ means one to eight carbon atoms). Examples of alkyl groups includemethyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl,sec-butyl, cyclohexyl, cyclopentyl, (cyclohexyl)methyl,cyclopropylmethyl and the like.

“Cycloalkyl” refers to hydrocarbon rings having the indicated number ofring atoms (e.g., C₃₋₆cycloalkyl) and being fully saturated or having nomore than one double bond between ring vertices. “Cycloalkyl” is alsomeant to refer to bicyclic and polycyclic hydrocarbon rings such as, forexample, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc.

“Alkylene” by itself or as part of another substituent means a divalentradical derived from an alkane, as exemplified by —CH₂CH₂CH₂CH₂—.Typically, alkyl (or alkylene) groups having 8 or fewer carbon atoms arepreferred in the present invention.

“Alkenyl” refers to an unsaturated hydrocarbon group which may belinear, cyclic or branched or a combination thereof. Alkenyl groups with2-8 carbon atoms are preferred. The alkenyl group may contain 1, 2 or 3carbon-carbon double bonds. Examples of alkenyl groups include ethenyl,n-propenyl, isopropenyl, n-but-2-enyl, n-hex-3-enyl and the like.

“Alkoxy” and “alkylthio” (or thioalkoxy) are used in their conventionalsense and refer to an alkyl groups attached to the remainder of themolecule via an oxygen atom or a sulfur atom, respectively. Examples ofalkoxy and thioalkoxy include methoxy, ethoxy, isopropoxy, butoxy,cyclopentyloxy, thiomethoxy, and the like.

“Alkynyl” refers to an unsaturated hydrocarbon group which may belinear, cyclic or branched or a combination thereof. Alkynyl groups with2-8 carbon atoms are preferred. The alkynyl group may contain 1, 2 or 3carbon-carbon triple bonds. Examples of alkynyl groups include ethynyl,n-propynyl, n-but-2-ynyl, n-hex-3-ynyl and the like.

“Aryl” refers to a polyunsaturated, aromatic hydrocarbon group having asingle ring or multiple rings which are fused together or linkedcovalently. Aryl groups with 6-10 carbon atoms are preferred. Examplesof aryl groups include phenyl and naphthalene-1-yl, naphthalene-2-yl,biphenyl and the like.

“Halo” or “halogen”, by itself or as part of a substituent refers to achlorine, bromine, iodine, or fluorine atom. Additionally, “haloalkyl”refers to a monohaloalkyl or polyhaloalkyl group, most typicallysubstituted with from 1-3 halogen atoms. Examples include 1-chloroethyl,3-bromopropyl, trifluoromethyl and the like.

“Heterocyclyl” refers to a saturated or unsaturated non-aromatic groupcontaining at least one heteroatom. “Heteroaryl” refers to an aromaticgroup containing at least one heteroatom. Each heterocyclyl andheteroaryl can be attached at any available ring carbon or heteroatom.Each heterocyclyl and heteroaryl may have one or more rings. Whenmultiple rings are present, they can be fused together or linkedcovalently. Each heterocyclyl and heteroaryl must contain at least oneheteroatom (typically 1 to 5 heteroatoms) selected from nitrogen, oxygenor sulfur. Preferably, these groups contain 0-3 nitrogen atoms, 0-1sulfur atoms and 0-1 oxygen atoms. Examples of saturated and unsaturatedheterocyclyl groups include pyrrolidine, imidazolidine, pyrazolidine,piperidine, 1,4-dioxane, morpholine, thiomorpholine, piperazine,3-pyrroline and the like. Examples of unsaturated and aromaticheterocycyl groups include pyrrole, imidazole, thiazole, oxazole, furan,thiophene, triazole, tetrazole, oxadiazole, pyrazole, isoxazole,isothiazole, pyridine, pyrazine, pyridazine, pyrimidine, triazine,indole, benzofuran, benzothiophene, benzimidazole, benzopyrazole,benzthiazole, quinoline, isoquinoline, quinazoline, quinoxaline and thelike. Heterocyclyl and heteroaryl groups can be unsubstituted orsubstituted. For substituted groups, the substitution may be on a carbonor heteroatom. For example, when the substitution is ═O, the resultinggroup may have either a carbonyl (—C(O)—) or a N-oxide (—N(O)—).

Suitable substituents for substituted alkyl, substituted alkenyl,substituted alkynyl and substituted cycloalkyl include -halogen, —OR′,—NR′R″, —SR′, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″,—OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —S(O)R′,—S(O)₂R′, —S(O)₂NR′R″, —NR′S(O)₂R″, —CN, oxo (═O or —O—) and —NO₂ in anumber ranging from zero to (2m′+1), where m′ is the total number ofcarbon atoms in such radical.

Suitable substituents for substituted aryl, substituted heteroaryl andsubstituted heterocyclyl include -halogen, unsubstituted or substitutedalkyl, unsubstituted or substituted alkenyl, unsubstituted orsubstituted alkynyl, unsubstituted or substituted cycloalkyl, —OR′, oxo(═O or —O), —OC(O)R′, —NR′R″, —SR′, —R′, —CN, —NO₂, —CO₂R′, —CONR′R″,—C(O)R′, —OC(O)NR′R″, —NR″C(O)R′, —NR″C(O)₂R′, —NR′—C(O)NR″R′″,—NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —S(O)R′, —S(O)₂R′,—S(O)₂NR′R″, —NR′S(O)₂R″ and —N₃ in a number ranging from zero to thetotal number of open valences on the aromatic ring system.

As used above, R′, R″ and R′″ each independently refer to a variety ofgroups including hydrogen, halogen, unsubstituted or substituted C₁₋₈alkyl, unsubstituted or substituted C₃₋₆ cycloalkyl, unsubstituted orsubstituted C₂₋₈ alkenyl, unsubstituted or substituted C₂₋₈ alkynyl,unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted heterocyclyl. Preferably, R′,R″ and R′″ independently refer to a variety of groups selected from thegroup consisting of hydrogen, unsubstituted C₁₋₈ alkyl, unsubstitutedheteroalkyl, unsubstituted aryl, aryl substituted with 1-3 halogens,unsubstituted C₁₋₈ alkyl, unsubstituted C₁₋₈ alkoxy, unsubstituted C₁₋₈thioalkoxy groups, or unsubstituted aryl-C₁₋₄ alkyl groups. When R′ andR″ are attached to the same nitrogen atom, they can be combined with thenitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring (for example,—NR′R″ includes 1-pyrrolidinyl and 4-morpholinyl).

Alternatively, two of the substituents on adjacent atoms of the aryl,heteroaryl or heterocycyl ring may optionally be replaced with asubstituent of the formula -T-C(O)—(CH₂)_(q)—U—, wherein T and U areindependently —NR′—, —O—, —CH₂— or a single bond, and q is an integer offrom 0 to 2. Alternatively, two of the substituents on adjacent atoms ofthe aryl or heteroaryl ring may optionally be replaced with asubstituent of the formula -A-(CH₂)_(r)—B—, wherein A and B areindependently —CH₂, —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or asingle bond, and r is an integer of from 1 to 3. One of the single bondsof the new ring so formed may optionally be replaced with a double bond.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula —(CH₂)_(s)—X—(CH₂)_(t)—, where s and t are independentlyintegers of from 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or—S(O)₂NR′—. The substituent R′ in —NR′— and —S(O)₂NR′— is selected fromhydrogen or unsubstituted C₁₋₆ alkyl.

“Heteroatom” is meant to include oxygen (O), nitrogen (N), sulfur (S)and silicon (Si).

“Pharmaceutically acceptable” carrier, diluent, or excipient is acarrier, diluent, or excipient compatible with the other ingredients ofthe formulation and not deleterious to the recipient thereof.

“Pharmaceutically-acceptable salt” refers to a salt which is acceptablefor administration to a patient, such as a mammal (e.g., salts havingacceptable mammalian safety for a given dosage regime). Such salts canbe derived from pharmaceutically-acceptable inorganic or organic basesand from pharmaceutically-acceptable inorganic or organic acids,depending on the particular substituents found on the compoundsdescribed herein. When compounds of the present invention containrelatively acidic functionalities, base addition salts can be obtainedby contacting the neutral form of such compounds with a sufficientamount of the desired base, either neat or in a suitable inert solvent.Salts derived from pharmaceutically-acceptable inorganic bases includealuminum, ammonium, calcium, copper, ferric, ferrous, lithium,magnesium, manganic, manganous, potassium, sodium, zinc and the like.Salts derived from pharmaceutically-acceptable organic bases includesalts of primary, secondary, tertiary and quaternary amines, includingsubstituted amines, cyclic amines, naturally-occurring amines and thelike, such as arginine, betaine, caffeine, choline,N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lysine, methylglucamine, morpholine,piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine, tromethamineand the like. When compounds of the present invention contain relativelybasic functionalities, acid addition salts can be obtained by contactingthe neutral form of such compounds with a sufficient amount of thedesired acid, either neat or in a suitable inert solvent. Salts derivedfrom pharmaceutically-acceptable acids include acetic, ascorbic,benzenesulfonic, benzoic, camphosulfonic, citric, ethanesulfonic,fumaric, gluconic, glucoronic, glutamic, hippuric, hydrobromic,hydrochloric, isethionic, lactic, lactobionic, maleic, malic, mandelic,methanesulfonic, mucic, naphthalenesulfonic, nicotinic, nitric, pamoic,pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonicand the like.

Also included are salts of amino acids such as arginate and the like,and salts of organic acids like glucuronic or galactunoric acids and thelike (see, for example, Berge, S. M., et al, “Pharmaceutical Salts”, J.Pharmaceutical Science, 1977, 66:1-19). Certain specific compounds ofthe present invention contain both basic and acidic functionalities thatallow the compounds to be converted into either base or acid additionsalts.

The neutral forms of the compounds may be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the present invention.

“Salt thereof” refers to a compound formed when the hydrogen of an acidis replaced by a cation, such as a metal cation or an organic cation andthe like. Preferably, the salt is a pharmaceutically-acceptable salt,although this is not required for salts of intermediate compounds whichare not intended for administration to a patient.

In addition to salt forms, the present invention provides compoundswhich are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Additionally, prodrugs can be converted to the compounds ofthe present invention by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

“Therapeutically effective amount” refers to an amount sufficient toeffect treatment when administered to a patient in need of treatment.

“Treating” or “treatment” as used herein refers to the treating ortreatment of a disease or medical condition (such as a bacterialinfection) in a patient, such as a mammal (particularly a human or acompanion animal) which includes:

ameliorating the disease or medical condition, i.e., eliminating orcausing regression of the disease or medical condition in a patient;

suppressing the disease or medical condition, i.e., slowing or arrestingthe development of the disease or medical condition in a patient; or

alleviating the symptoms of the disease or medical condition in apatient.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, bothsolvated forms and unsolvated forms are intended to be encompassedwithin the scope of the present invention. Certain compounds of thepresent invention may exist in multiple crystalline or amorphous forms(i.e., as polymorphs). In general, all physical forms are equivalent forthe uses contemplated by the present invention and are intended to bewithin the scope of the present invention.

Certain compounds of the present invention possess asymmetric carbonatoms (optical centers) or double bonds; the racemates, diastereomers,geometric isomers and individual isomers (e.g., separate enantiomers)are all intended to be encompassed within the scope of the presentinvention. The compounds of the present invention may also containunnatural proportions of atomic isotopes at one or more of the atomsthat constitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present invention, whether radioactive or not, areintended to be encompassed within the scope of the present invention.

Compounds that Modulate CCR9 Activity

The present invention provides compounds that modulate CCR9 activity.Specifically, the invention provides compounds having anti-inflammatoryor immunoregulatory activity. The compounds of the invention are thoughtto interfere with inappropriate T-cell trafficking by specificallymodulating or inhibiting a chemokine receptor function. Chemokinereceptors are integral membrane proteins which interact with anextracellular ligand, such as a chemokine, and mediate a cellularresponse to the ligand, e.g., chemotaxis, increased intracellularcalcium ion concentration, etc. Therefore, modulation of a chemokinereceptor function, e.g., interference with a chemokine receptor ligandinteraction, will modulate a chemokine receptor mediated response, andtreat or prevent a chemokine receptor mediated condition or disease.Modulation of a chemokine receptor function includes both inducement andinhibition of the function. The type of modulation accomplished willdepend on the characteristics of the compound, i.e., antagonist or full,partial or inverse agonist.

Without intending to be bound by any particular theory, it is believedthat the compounds provided herein interfere with the interactionbetween a chemokine receptor and one or more cognate ligands. Inparticular, it is believed that the compounds interfere with theinteraction between CCR9 and a CCR9 ligand, such as TECK. Compoundscontemplated by the invention include, but are not limited to, theexemplary compounds provided herein and salts thereof.

For example, compounds of this invention act as potent CCR9 antagonists,and this antagonistic activity has been further confirmed in animaltesting for inflammation, one of the hallmark disease states for CCR9.Accordingly, the compounds provided herein are useful in pharmaceuticalcompositions, methods for the treatment of CCR9-mediated diseases, andas controls in assays for the identification of competitive CCR9antagonists.

CCR9 Antagonists as Treatments of Cancer

In additional to inflammatory diseases, cancers that are caused byuncontrolled proliferation of T cells may be treated with a CCR9antagonist. Certain types of cancer are caused by T cells expressingchemokine receptor CCR9. For example, thymoma and thymic carcinoma arediseases in which cancer cells are found in the tissues of the thymus,an organ where lymphocyte development occurs. T cells in the thymus,called thymocytes, are known to express functional CCR9; its ligand ishighly expressed in the thymus. Another example is the acute lymphocyticleukemia (ALL), also called acute lymphoblastic leukemia and acute, is acommon leukemia, which can occur in children as well as adults. Recentstudies have shown that T cells in patients with ALL selectively expresshigh level of CCR9 (Qiuping Z et al., Cancer Res. 2003, 1;63(19):6469-77)

Chemokine receptors have been implicated in cancer. Although the exactmechanisms of chemokine receptors' involvements have yet to be fullunderstood, such receptors are known to promote the growth of cancercells (proliferation), facilitate the spread of cancer cells(metastasis) or help them resist program cell death (apoptosis). Forexample, CCR9 in a cancer T cell line MOLT-4 provides the cells with asurvival signal, allowing them to resist apoptosis (Youn B S, et al.,Apoptosis. 2002 June; 7(3):271-6). In the cases of thymoma, thymiccarcinoma and acute lymphocytic leukemia, it is likely that CCR9 plays akey in the survival and proliferation these cells. Thus, blocking thesignaling of CCR9 should help prevent their expansion and metastasis.

Compounds of the Invention

The compounds provided herein have the general formula (I):

X Substituents

X represents from 1 to 4 substituents independently selected from thegroup consisting of halogen, —CN, —NO₂, —OH, —OR¹, —C(O)R¹, —CO₂R¹,—O(CO)R¹, —C(O)NR¹R², —OC(O)NR¹R², —SR¹, —SOR¹, —SO₂R¹, —SO₂NR¹R²,—NR¹R², —NR¹C(O)R², —NR¹C(O)R², —NR¹SO₂R², —NR¹(CO)NR¹R², unsubstitutedor substituted C₁₋₈ alkyl, unsubstituted or substituted C₂₋₈ alkenyl,unsubstituted or substituted C₂₋₈ alkynyl, unsubstituted or substitutedC₃₋₈ cycloalkyl, unsubstituted or substituted C₆₋₁₀ aryl, unsubstitutedor substituted 5- to 10-membered heteroaryl, and unsubstituted orsubstituted 3- to 10-membered heterocyclyl.

When X is substituted C₁₋₈alkyl, substituted C₃₋₈ cycloalkyl,substituted C₂₋₈ alkenyl, or substituted C₂₋₈ alkynyl, it may have from1-5 substituents independently selected from the group consisting ofhalogen, —OH, —CN, —NO₂, ═O, —OC(O)R¹, —OR¹, —C(O)R¹, —CONR¹R²,—OC(O)NR¹R², —NR²C(O)R¹, —NR¹C(O)NR²R³, —CO₂R¹, —NR¹R², —NR²CO₂R¹, —SR¹,—SOR¹, —SO₂R¹, —SO₂NR¹R², —NR¹SO₂R², unsubstituted or substituted aryl,unsubstituted or substituted heteroaryl, and unsubstituted orsubstituted heterocyclyl.

When X is substituted C₆₋₁₀ aryl, substituted 5- to 10-memberedheteroaryl, or substituted 3- to 10-membered heterocyclyl, it may havefrom 1-4 substituents independently selected from the group consistingof halogen, unsubstituted or substituted C₁₋₈ alkyl, unsubstituted orsubstituted C₁₋₈ haloalkyl, —CN, —NO₂, —OH, —OR¹, ═O, —OC(O)R¹, —CO₂R¹,—C(O)R¹, —CONR¹R², —OC(O)NR¹R², —NR²C(O)R¹, —NR¹C(O)NR²R³, —NR¹R²,—NR²CO₂R¹, —SR¹, —SOR¹, —SO₂R¹, —SO₂NR¹R², and —NR¹SO₂R². Suitablesubstituted C₁₋₈ alkyl include those defined above in paragraph [0051].

R¹, R² and R³ are each independently selected from the group consistingof hydrogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀aryl, 5- to 10-membered heteroaryl, aryl-C₁₋₄ alkyl,aryl-C₁₋₄ alkyl, and aryloxy-C₁₋₄ alkyl. Each can be unsubstituted orsubstituted with from 1-3 substituents independently selected from thegroup consisting of halogen, —OH, —OR′, —OCOHNR′, —OCONR′₂, —SH, —SR′,—SO₂NH₂, —CONH₂, —NHC(O)NH₂, NR′C(O)NH₂, —CO₂H, —CN, —NO₂, —NH₂, —NHR′and —NR′₂, —S(O)R′, —S(O)₂R′, —CO₂R′, —CONR′₂, —CONHR′, —C(O)R′,—NR′COR′, —NHCOR′, —NR′CO₂R′, —NHCO₂R′, —CO₂R′, —NR′C(O)NR′₂,—NHC(O)NR′₂, —NR′C(O)NHR′, —NHC(O)NHR′, —NR′SO₂R′, —NHSO₂R′, —SO₂NR′₂,and —SO₂NHR′. Alternatively, two of R¹, R² and R³ together with theatom(s) to which they are attached, may form a 5-, 6- or 7-memberedring.

Y Substituents

Y represents from 1 to 3 substituents, each independently selected fromthe group consisting of halogen, —CN, —NO₂, —OH, —OR⁴, —C(O)R⁴, —CO₂R⁴,—SR⁴, —SOR⁴, —SO₂R⁴, and unsubstituted or substituted C₁₋₄ alkyl.

When Y is a substituted C₁₋₄ alkyl, it may have from 1 to 3 substituentsindependently selected from the group consisting of halogen, —OH, —OR⁴,—CN, —NO₂, ═O, —OC(O)R⁴, —CO₂R⁴, —C(O)R⁴, —CONR⁴R⁵, —OC(O)NR⁴R⁵,—NR⁴C(O)R⁵, —NR⁴C(O)NR⁵R⁶, —NR⁴R⁵, —NR⁴CO₂R⁵, —SR⁴, —SOR⁴, —SO₂R⁴,—SO₂NR⁴R⁵, and —NR⁴SO₂R⁵.

R⁴, R⁵ and R⁶ are each independently selected from the group consistingof hydrogen, unsubstituted or substituted C₁₋₆ haloalkyl, unsubstitutedor substituted C₁₋₆ alkyl, unsubstituted or substituted C₃₋₆ cycloalkyl,unsubstituted or substituted C₂₋₆alkenyl, and unsubstituted orsubstituted C₂₋₆ alkynyl. Each can be unsubstituted or substituted withfrom 1 to 3 substituents independently selected from the groupconsisting of —OH, —OR′, —SH, —SR′, —CN, —NO₂, —NH₂, —NHR′, —NR′₂,—S(O)R′, —S(O)₂R′, —CO₂R′, —CONHR′, —CONR′₂, and —C(O)R′. Additionally,two of R⁴, R⁵ and R⁶ together with the atom(s) to which they areattached, may form a 5-, 6- or 7-membered ring.

Linkers

L is —C(O)—, —S—, —SO— or —S(O)₂—.

Z Substituents

Z represents either unsubstituted or substituted monocyclic or bicyclicC₅₋₁₀ heteroaryl or unsubstituted or substituted monocyclic or bicyclicC₃₋₁₀ heterocyclyl.

When Z is a substituted heteroaryl or substituted heterocyclyl, it mayhave from 1 to 5 substituents independently selected from the groupconsisting of halogen, unsubstituted or substituted C₁₋₈ alkyl,unsubstituted or substituted C₁₋₈ cycloalkyl, unsubstituted orsubstituted C₂₋₈ alkenyl, unsubstituted or substituted C₂₋₈ alkynyl,unsubstituted or substituted C₁₋₈ alkoxy, ═O, —CN, —NO₂, —OH, —OR⁷,—OC(O)R⁷, —CO₂R⁷, —C(O)R⁷, —CONR⁷R⁸, —OC(O)NR⁷R⁸, —NR⁷C(O)R⁸,—NR⁷C(O)NR⁸R⁹, —NR⁷R⁸, —NR⁷CO₂R⁸, —SR⁷, —SOR⁷, —SO₂R⁷, —SO₂NR⁷R⁸,—NR⁷SO₂R⁸, unsubstituted or substituted C₆₋₁₀ aryl, unsubstituted orsubstituted heteroaryl and unsubstituted or substituted heterocyclyl.

Suitable substituted C₁₋₈ alkyl, C₃₋₈ cycloalkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl and C₁₋₈ alkoxy substituents on Z may have from 1 to 5substituents independently selected from the group consisting ofhalogen, —OH, —OR⁷, —CN, —NO₂, ═O, —CN, —NO₂, —OC(O)R⁷, —CO₂R⁷, —C(O)R⁷,—CONR⁷R⁸, —OC(O)NR⁷R⁸, —NR⁷C(O)R⁸, —NR⁷C(O)NR⁸R⁹, —NR⁷R⁸, —NR⁷CO₂R⁸,—SR⁷, —SOR⁷, —SO₂R⁷, —SO₂NR⁷R⁸, —NR⁷SO₂R⁸, unsubstituted or substitutedphenyl, unsubstituted or substituted 5- or 6-membered heteroaryl, orunsubstituted or substituted 3- to 6-membered heterocyclyl.

Suitable substituted aryl, heteroaryl and heterocyclyl substituents on Zmay have from 1 to 5 substituents independently selected from the groupconsisting of halogen, —OH, —OR⁷, —CN, —NO₂, ═O, —CN, —NO₂,—OC(O)R⁷—OC(O)R⁷, —CO₂R⁷, —C(O)R⁷, —CONR⁷R⁸, —OC(O)NR⁷R⁸, —NR⁷C(O)R⁸,—NR⁷C(O)NR⁸R⁹, —NR⁷R⁸, —NR⁷CO₂R⁸, —SR⁷, —SOR⁷, —SO₂R⁷, —SO₂NR⁷R⁸,—NR⁷SO₂R⁸ and unsubstituted or substituted C₃₋₆ heterocyclyl.

R⁷, R⁸ and R⁹ are each independently hydrogen, unsubstituted orsubstituted C₁₋₆ haloalkyl, unsubstituted or substituted C₁₋₆ alkyl,unsubstituted or substituted C₃₋₆ cycloalkyl, unsubstituted orsubstituted C₂₋₆ alkenyl, unsubstituted or substituted C₂₋₆ alkynyl,unsubstituted or substituted phenyl or unsubstituted or substitutedheteroaryl, unsubstituted or substituted aryl-C₁₋₄ alkyl, andunsubstituted or substituted aryloxy-C₁₋₄ alkyl. Each can be substitutedwith from 1 to 3 substituents independently selected from the groupconsisting of halogen, —OH, —OR′, —OCONHR′, —OCONR′₂, —SH, —SR′,—SO₂NH₂, —CONH₂, —NHC(O)NH₂, NR′C(O)NH₂, —CO₂H, —CN, —NO₂, —NH₂, —NHR′and —NR′₂, —S(O)R′, —S(O)₂R′, —CO₂R′, —CONR′₂, —CONHR′, —C(O)R′,—NR′COR′, —NHCOR′, —NR′CO₂R′, —NHCO₂R′, —CO₂R′, —NR′C(O)NR′₂,—NHC(O)NR′₂, —NR′C(O)NHR′, —NHC(O)NHR′, —NR′SO₂R′, —NHSO₂R′, —SO₂NR′₂,and —SO₂NHR′. R′ is defined above. It is preferably, unsubstituted orsubstituted C₁₋₆ alkyl. Alternatively, two of R⁷, R⁸ and R⁹ togetherwith the atom(s) to which they are attached, may form a 5-, 6- or7-membered ring.

Known Compounds

Compounds of the formula (I) where X is methyl when Z is 2-thiophene,2-(3-hydroxy-1H-indole) or 3-(1-methylpyridinium) are known, but not asCCR9 antagonists.

Preferred X Substituents

X preferably represents from 1 to 3 substituents independently selectedfrom the group consisting of halogen, —CN, —NO₂, —OH, —OR¹, —C(O)R¹,—CO₂R′, —O(CO)R¹, —OC(O)NR¹R², —SR¹, —SOR¹, —SO₂R¹, —NR¹R², —NR¹C(O)R²,—NR¹C(O)₂R², —NR¹(CO)NR¹R², unsubstituted or substituted C₁₋₈ alkyl,unsubstituted or substituted C₂₋₈ alkenyl, unsubstituted or substitutedC₂₋₈ alkynyl, unsubstituted or substituted C₃₋₈ cycloalkyl,unsubstituted or substituted C₆₋₁₀ aryl, unsubstituted or substituted 5-or 6-membered heteroaryl, or unsubstituted or substituted 4- to7-membered heterocyclyl.

X more preferably represents 1 or 2 substituents independently selectedfrom the group consisting of —NO₂, —OR¹, —C(O)R¹, —SO₂R¹, —NR¹R²,unsubstituted or substituted C₁₋₈ alkyl, unsubstituted or substitutedphenyl, unsubstituted or substituted 5- or 6-membered heteroaryl, orunsubstituted or substituted 5- or 6-membered heterocyclyl. Morepreferably, at least one X substituent is situated para to thesulfonamido bond as defined in formula (I).

When X is substituted C₁₋₈ alkyl or substituted C₃₋₈ cycloalkyl, itpreferably has from 1 to 3 substituents independently selected from thegroup consisting of halogen, —OH, —CN, ═O, —OC(O)R¹, —OR¹, —C(O)R¹,—CONR¹R², —NR²C(O)R¹, —CO₂R′, —NR¹R², —SR¹, —SOR¹, —SO₂R¹, —NR¹SO₂R²,unsubstituted or substituted aryl, and unsubstituted or substitutedheteroaryl. When X is a substituted C₁₋₈ alkyl, it more preferably hasfrom 1 to 3 substituents independently selected from the groupconsisting of halogen, —OH, —CN, ═O, —OC(O)R¹, —OR¹, —C(O)R¹, —CONR¹R²,—NR²C(O)R¹, —CO₂R¹, —NR¹R², —SO₂R¹, unsubstituted or substituted aryl,and unsubstituted or substituted heteroaryl.

When X is substituted C₆₋₁₀ aryl or substituted heteroaryl, itpreferably has from 1 to 3 substituents independently selected from thegroup consisting of halogen, —CN, —OH, —OR¹, ═O, —OC(O)R¹, —CO₂R¹,—C(O)R¹, —CONR¹R², —NR²C(O)R¹, —NR¹R², —SR¹, —SOR¹, —SO₂R¹, —NR¹SO₂R²,unsubstituted or substituted C₁₋₈ alkyl, and C₁₋₈ unsubstituted orsubstituted haloalkyl. When X is a substituted phenyl or substituted 5-or 6-membered heteroaryl, it is more preferably has from 1 to 3substituents independently selected from the group consisting ofhalogen, —OH, —OR¹, —C(O)R¹, —CONR¹R², —NR²C(O)R¹, —NR¹R², —SO₂R¹,unsubstituted or substituted C₁₋₈ alkyl, and unsubstituted orsubstituted C₁₋₈ haloalkyl.

When X is a substituted 4- to 7-membered heterocyclyl, it preferably hasfrom 1 to 3 substituents independently selected from the groupconsisting of unsubstituted or substituted C₁₋₈ alkyl, C₁₋₈ haloalkyl,—OR¹, —OH, —OC(O)R¹, —CO₂R¹, —C(O)R¹, —CONR¹R², —NR¹R², —SO₂R¹, and—NR¹SO₂R². When X is a 5- or 6-membered heterocyclyl, it more preferablyhas 1 to 2 substituents independently selected from the group consistingof unsubstituted or substituted C₁₋₈ alkyl, unsubstituted or substitutedC₁₋₈ haloalkyl, unsubstituted or substituted C₁₋₈ haloalkyl, —OR¹, —OH,—C(O)R¹, —CONR¹R², —NR¹R², and —SO₂R¹.

Preferred Y Substituents

Y preferably represents from 1 to 3 substituents independently selectedfrom the group consisting of halogen, —CN, —NO₂, —OR⁴, —C(O)R⁴, —SR⁴,—CF₃, —SOR⁴, and —SO₂R⁴. Y more preferably represents from 1 to 3substituents independently selected from the group consisting ofhalogen, —CN, —NO₂, —CF₃, and —SO₂R⁴. Y most preferably represents 1 or2 substituents where at least halogen is present and optionally anothersubstituent selected from the group consisting of —CN, —NO₂, —OH, —OR⁴,—C(O)R⁴, —CO₂R⁴, —SR⁴, —SOR⁴, —SO₂R⁴ and unsubstituted or substitutedC₁₋₄ alkyl. Most preferably, at least one Y substituent is located parato the sulfonamide bond as defined in formula (I), and one Y substituentis halogen.

When Y is substituted alkyl, it preferably has from 1 to 3 substituentsindependently selected from the group consisting of halogen, —OH, —OR⁴,—CN, —NO₂, ═O, —OC(O)R⁴, —CO₂R⁴, —C(O)R⁴, —CONR⁴R⁵, —NR⁴C(O)R⁵, —NR⁴R⁵,—NR⁴, —SR⁴, —SOR⁴, —SO₂R⁴, and —NR⁴SO₂R⁵.

Preferred Linkers

L is preferably —C(O)—.

Preferred Z Substituents

Z preferably represents an unsubstituted or substituted 5- or 6-memberedheteroaryl.

When Z is a substituted 5- or 6-membered heteroaryl, it preferably hasfrom 1 to 3 substituents independently selected from the groupconsisting of halogen, unsubstituted or substituted C₁₋₄ alkyl,unsubstituted or substituted C₃₋₈ cycloalkyl, unsubstituted orsubstituted C₂₋₈ alkenyl, unsubstituted or substituted C₂₋₈ alkynyl,unsubstituted or substituted C₁₋₈ alkoxy, ═O, —CN, —NO₂, —OH, —OR⁷,—OC(O)R⁷—CO₂R⁷, —C(O)R⁷, —CONR⁷R⁸—NR⁷C(O)R⁸, —NR⁷R⁸, —SR⁷, —SOR⁷,—SO₂R⁷, —SO₂NR⁷R⁸, —NR⁷SO₂R⁸, unsubstituted or substituted phenyl,unsubstituted or substituted 5- or 6-membered heteroaryl, andunsubstituted or substituted 3- to 7-membered heterocyclyl. If present,one substituent is preferably located ortho to one of the heteroatoms inthe ring or is directly connected to a ring heteroatom.

Z more preferably represents unsubstituted or substituted 6-memberedheteroaryl with carbon and up to 3 nitrogen atoms and with from 1 to 3substituents independently selected from the group consisting ofhalogen, C₁₋₈ alkyl, C₃₋₈ cycloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,C₁₋₈alkoxy, ═O, —CN, —NO₂, —OH, —OR⁷, —OC(O)R⁷, —CO₂R⁷, —C(O)R⁷,—CONR⁷R⁸, —NR⁷C(O)R⁸, —NR⁷R⁸, —SR⁷, —SOR⁷, —SO₂R⁷, —SO₂NR⁷R⁸, —NR⁷SO₂R⁸,unsubstituted or substituted phenyl, unsubstituted or substituted 5- and6-membered heteroaryl, and unsubstituted or substituted 3- to 6-memberedheterocyclyl. In this embodiment, Z can be any unsubstituted orsubstituted chemically allowed regioisomers of pyridyl, pyrimidinyl,pyridazinyl, pyrazinyl and the like and their respective N-oxides. Inpreferred embodiments, Z is pyridinyl with from 0 to 3 substituents;pyrimidinyl with from 0 to 3 substituents; pyrazinyl with from 0 to 3substituents; or pyridazinyl with from 0 to 3 substituents (especially,where one ring nitrogen has a ═O substituent).

Z most preferably represents unsubstituted or substituted 6-memberedheteroaryl with carbon and 1 to 2 nitrogen atoms and with 1 or 2substituents independently selected from the group consisting ofhalogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, ═O, —CN, —NO₂, —OH, —OR⁷, —C(O)R⁷,—CONR⁷R⁸, —NR⁷C(O)R⁸, —NR⁷R⁸, —SR⁷, —SOR⁷, —SO₂R⁷, —SO₂NR⁷R⁸, —NR⁷SO₂R⁸,5- or 6-membered heteroaryl and a 3- to 7-membered heterocyclyl. In thisembodiment, Z can be any chemically allowed regioisomers of pyridyl,pyrimidinyl, pyridazinyl, pyrazinyl and the like, and their respectiveN-oxides.

When the substituent on Z is substituted C₁₋₈ alkyl, substituted C₃₋₈cycloalkyl, substituted C₂₋₈ alkenyl, substituted C₂₋₈ alkynyl orsubstituted C₁₋₈ alkoxy groups, it preferably has from 1 to 3substituents independently selected from the group consisting ofhalogen, —OH, —OR⁷, ═O, —CO₂R⁷, —C(O)R⁷, —CONR⁷R⁸, —NR⁷C(O)R⁸, —NR⁷R⁸,—SR⁷, —SOR⁷, —SO₂R⁷, —NR⁷SO₂R⁸, unsubstituted or substituted phenyl,unsubstituted or substituted 5- or 6-membered heteroaryl, andunsubstituted or substituted 3- to 6-membered heterocyclyl. Morepreferably, it has from 1 to 3 substituents independently selected fromthe group consisting of halogen, —OH, —OR⁷, ═O, —C(O)R⁷, —CO₂R⁷,—CONR⁷R⁸, —NR⁷C(O)R⁸, —NR⁷R⁸, —SR⁷, —SOR⁷, —SO₂R⁷, —SO₂NR⁷R⁸, —NR⁷SO₂R⁸,and 3- to 6-membered heterocyclyl.

When the substituent on Z is substituted phenyl or substitutedheteroaryl, it preferably has from 1 to 3 substituents independentlyselected from the group consisting of halogen, —OH, —OR⁷, —CN, —NO₂, ═O,—CN, —NO₂, —OC(O)R⁷, —CO₂R⁷, —C(O)R⁷, —CONR⁷R⁸, —NR⁷C(O)R⁸, —NR⁷R⁸,—SR⁷, —SOR⁷, —SO₂R⁷, —NR⁷SO₂R⁸, unsubstituted or substituted C₁₋₈ alkyl,unsubstituted or substituted C₁₋₈ haloalkyl, unsubstituted orsubstituted C₃₋₈ cycloalkyl, and 3- to 6-membered heterocyclyl.

When the substituent on Z is substituted heterocyclyl, it preferably hasfrom 1 to 2 substituents independently selected from the groupconsisting of unsubstituted or substituted C₁₋₈ alkyl, C₁₋₈ haloalkyl,—OR⁷, —OH, —C(O)R⁷, —CONR⁷R⁸, —NR⁷R⁸, and —SO₂R⁷.

Preferred Compounds

In several preferred embodiments, the compounds are represented by thefollowing formulae:

In each of the above formulae, X′ and X″ are each independently selectedfrom the group consisting of hydrogen, halogen, —CN, —NO₂, —OH, —OR¹,—C(O)R¹, —CO₂R¹, —O(CO)R¹, —C(O)NR¹R², —OC(O)NR¹R², —SR¹, —SOR¹, —SO₂R¹,—SO₂NR¹R², —NR¹R², —NR¹C(O)R², —NR¹C(O)₂R², —NR¹SO₂R², —NR¹(CO)NR¹R²,unsubstituted or substituted C₁₋₈ alkyl, unsubstituted or substitutedC₁₋₈ haloalkyl, unsubstituted or substituted C₂₋₈ alkenyl, unsubstitutedor substituted C₂₋₈ alkynyl, unsubstituted or substituted C₃₋₈cycloalkyl, unsubstituted or substituted C₆₋₁₀ aryl, unsubstituted orsubstituted 5- to 10-membered heteroaryl, and unsubstituted orsubstituted 3- to 10-membered heterocyclyl, with the proviso that X′ andX″ cannot both be hydrogen simultaneously.

In one preferred embodiment, X′ and X″ are each independently selectedfrom the group consisting of hydrogen, —NO₂, —OR¹, —C(O)R¹, —SO₂R¹,—NR¹R², unsubstituted or substituted C₁₋₈ alkyl, unsubstituted orsubstituted C₁₋₈ haloalkyl, unsubstituted or substituted C₃₋₈cycloalkyl, unsubstituted or substituted C₂₋₈ alkenyl, unsubstituted orsubstituted phenyl, unsubstituted or substituted 5- or 6-memberedheteroaryl, unsubstituted or substituted 5- or 6-membered heterocyclyl,with the proviso that X′ and X″ cannot both be hydrogen simultaneously.

In another preferred embodiment, X′ and X″ are each independentlyselected from the group consisting of hydrogen, —CF₃, —CH═CH₂, isoamyl,phenylacetylene, t-butyl, ethyl (Et), i-propyl (^(i)Pr), —C(CH₃)₂CH₂CH₃,hydroxybutyl, —C(CH₃)₂CH₂CH₂OH, —CH₂CH₂CO₂Me, —OCF₃, —OMe, —O—^(i)Pr,—C(O)Me, —SO₂Me, phenyl (Ph), —OEt, pyrazole, oxazole, and morpholinyl,with the proviso that X′ and X″ cannot both be hydrogen simultaneously.

In each of the above formulae, Y′ and Y″ are each independently selectedfrom the group consisting of hydrogen, halogen, —CN, —NO₂, —OH, —OR⁴,—C(O)R⁴, —CO₂R⁴, —SR⁴, —SOR⁴, —SO₂R⁴, unsubstituted or substituted C₁₋₄alkyl, and unsubstituted or substituted C₁₋₄ haloalkyl, with the provisothat Y′ and Y″ cannot both be hydrogen simultaneously.

In one preferred embodiment, Y′ and Y″ are each independently hydrogenor halogen, with the proviso that one or both are halogen. Morepreferably, Y′ is hydrogen and Y″ is chloro; Y′ and Y″ are both fluoro;Y′ is hydrogen and Y″ is fluoro; or Y′ is hydrogen and Y″ is bromo. Mostpreferably, one halogen atom is para to the sulfonamide bond in formula(I).

In each of the above formulae, Z′ and Z″ are each independently selectedfrom the group consisting of hydrogen, halogen, unsubstituted orsubstituted C₁₋₈ alkyl, unsubstituted or substituted C₃₋₈ cycloalkyl,unsubstituted or substituted C₂₋₈ alkenyl, unsubstituted or substitutedC₂₋₈ alkynyl, unsubstituted or substituted C₁₋₈ alkoxy, ═O, —CN, —NO₂,—OH, —OR⁷, —OC(O)R⁷, —CO₂R⁷, —C(O)R⁷, —CONR⁷R⁸, —OC(O)NR⁷R⁸, —NR⁷C(O)R⁸,—NR⁷C(O)NR⁸R⁹, —NR⁷R⁸, —NR⁷CO₂R⁸, —SR⁷, —SOR⁷, —SO₂R⁷, —SO₂NR⁷R⁸,—NR⁷SO₂R⁸, unsubstituted or substituted C₁₋₁₀ aryl, unsubstituted orsubstituted 5- or 6-membered heteroaryl and unsubstituted or substituted3- to 7-membered heterocyclyl.

In one preferred embodiment, Z′ and Z″ are each independently selectedfrom the group consisting of hydrogen, halogen, unsubstituted orsubstituted C₁₋₈ alkyl, unsubstituted or substituted C₃₋₈ cycloalkyl,—CN, —OH, —OR⁷, —C(O)R⁷, —CO₂R⁷, —OC(O)R⁷, —CONR⁷R⁸, —NR⁷R⁸, —NR⁷CO₂R⁸,—SR⁷, —SOR⁷, —SO₂R⁷, —NR⁷SO₂R⁸, unsubstituted or substituted C₆₋₁₀ aryl,and unsubstituted or substituted 5- or 6-membered heteroaryl.

In a more preferred embodiment, Z′ and Z″ are each independentlyhydrogen, halogen, —CN, —OR⁷, —NR⁷R⁸, —SR⁷ (e.g., thiomethyl), —SOR⁷,and —SO₂R⁷ (e.g., methylsulfonyl), unsubstituted or substituted C₁₋₆alkoxyl (e.g., methoxy), unsubstituted or substituted C₁₋₆ alkyl (e.g.,methyl), unsubstituted or substituted phenyl, or unsubstituted orsubstituted 5- or 6-membered heterocyclyl.

Compositions that Modulate CCR9 Activity

In another aspect, the present invention provides compositions thatmodulate CCR9 activity. Generally, the compositions for modulatingchemokine receptor activity in humans and animals will comprise apharmaceutically acceptable excipient or diluent and a compound havingthe formula provided above as formula (I).

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. By“pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

The pharmaceutical compositions for the administration of the compoundsof this invention may conveniently be presented in unit dosage form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the pharmaceutical compositions are prepared byuniformly and intimately bringing the active ingredient into associationwith a liquid carrier or a finely divided solid carrier or both, andthen, if necessary, shaping the product into the desired formulation. Inthe pharmaceutical composition the active object compound is included inan amount sufficient to produce the desired effect upon the process orcondition of diseases.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions and self emulsifications as described in U.S. PatentApplication 20020012680, hard or soft capsules, or syrups or elixirs.Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions. Such compositions may contain one or more agents selectedfrom sweetening agents, flavoring agents, coloring agents and preservingagents in order to provide pharmaceutically elegant and palatablepreparations. Tablets contain the active ingredient in admixture withother non-toxic pharmaceutically acceptable excipients which aresuitable for the manufacture of tablets. These excipients may be, forexample, inert diluents such as cellulose, silicon dioxide, aluminumoxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example PVP, cellulose, PEG, starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coatedenterically or otherwise by known techniques to delay disintegration andabsorption in the gastrointestinal tract and thereby provide a sustainedaction over a longer period. For example, a time delay material such asglyceryl monostearate or glyceryl distearate may be employed. They mayalso be coated by the techniques described in the U.S. Pat. Nos.4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tabletsfor control release.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.Additionally, emulsions can be prepared with a non-water miscibleingredient such as oils and stabilized with surfactants such asmono-diglycerides, PEG esters and the like.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil in water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative. and flavoring and coloringagents. Oral solutions can be prepared in combination with, for example,cyclodextrin, PEG and surfactants.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, axed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of the present invention may also be administered in theform of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols. Additionally, the compounds can be administered viaoculardelivery by means of solutions or ointments. Still further, transdermaldelivery of the subject compounds can be accomplished by means ofiontophoretic patches and the like.

For topical use, creams, ointments, jellies, solutions or suspensionscontaining the compounds of the present invention are employed. As usedherein, topical application is also meant to include the use of mouthwashes and gargles.

The pharmaceutical compositions and methods of the present invention mayfurther comprise other therapeutically active compounds as noted herein,such as those applied in the treatment of the above mentionedpathological conditions.

Methods of Treating CCR9-Mediated Conditions or Diseases

In yet another aspect, the present invention provides methods oftreating or preventing a CCR9-mediated condition or disease byadministering to a subject having such a condition or disease atherapeutically effective amount of any compound of formula (I) above.Compounds for use in the present methods include those compoundsaccording to formula (I), those provided above as embodiments, thosespecifically exemplified in the Examples below, and those provided withspecific structures herein. The “subject” is defined herein to includeanimals such as mammals, including, but not limited to, primates (e.g.,humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice andthe like. In preferred embodiments, the subject is a human.

As used herein, the phrase “CCR9-mediated condition or disease” andrelated phrases and terms refer to a condition or disease characterizedby inappropriate, i.e., less than or greater than normal, CCR9functional activity. Inappropriate CCR9 functional activity might ariseas the result of CCR9 expression in cells which normally do not expressCCR9, increased CCR9 expression (leading to, e.g., inflammatory andimmunoregulatory disorders and diseases) or decreased CCR9 expression.Inappropriate CCR9 functional activity might also arise as the result ofTECK secretion by cells which normally do not secrete TECK, increasedTECK expression (leading to, e.g., inflammatory and immunoregulatorydisorders and diseases) or decreased TECK expression. A CCR9-mediatedcondition or disease may be completely or partially mediated byinappropriate CCR9 functional activity. However, a CCR9-mediatedcondition or disease is one in which modulation of CCR9 results in someeffect on the underlying condition or disease (e.g., a CCR9 antagonistresults in some improvement in patient well being in at least somepatients).

The term “therapeutically effective amount” means the amount of thesubject compound that will elicit the biological or medical response ofa cell, tissue, system, or animal, such as a human, that is being soughtby the researcher, veterinarian, medical doctor or other treatmentprovider.

Diseases and conditions associated with inflammation, immune disorders,infection and cancer can be treated or prevented with the presentcompounds, compositions, and methods. In one group of embodiments,diseases or conditions, including chronic diseases, of humans or otherspecies can be treated with inhibitors of CCR9 function. These diseasesor conditions include: (1) allergic diseases such as systemicanaphylaxis or hypersensitivity responses, drug allergies, insect stingallergies and food allergies, (2) inflammatory bowel diseases, such asCrohn's disease, ulcerative colitis, ileitis and enteritis, (3)vaginitis, (4) psoriasis and inflammatory dermatoses such as dermatitis,eczema, atopic dermatitis, allergic contact dermatitis, urticaria andpruritus, (5) vasculitis, (6) spondyloarthropathies, (7) scleroderma,(8) asthma and respiratory allergic diseases such as allergic asthma,allergic rhinitis, hypersensitivity lung diseases and the like, (9)autoimmune diseases, such as fibromyalagia, scleroderma, ankylosingspondylitis, juvenile RA, Still's disease, polyarticular juvenile RA,pauciarticular juvenile RA, polymyalgia rheumatica, rheumatoidarthritis, psoriatic arthritis, osteoarthritis, polyarticular arthritis,multiple sclerosis, systemic lupus erythematosus, type I diabetes, typeII diabetes, glomerulonephritis, and the like, (10) graft rejection(including allograft rejection), (11) graft-v-host disease (includingboth acute and chronic), (12) other diseases in which undesiredinflammatory responses are to be inhibited, such as atherosclerosis,myositis, neurodegenerative diseases (e.g., Alzheimer's disease),encephalitis, meningitis, hepatitis, nephritis, sepsis, sarcoidosis,allergic conjunctivitis, otitis, chronic obstructive pulmonary disease,sinusitis, Behcet's syndrome and gout, (13) immune mediated foodallergies such as Coeliac (Celiac) disease (14) pulmonary fibrosis andother fibrotic diseases, and (15) irritable bowel syndrome.

In another group of embodiments, diseases or conditions can be treatedwith modulators and agonists of CCR9 function. Examples of diseases tobe treated by modulating CCR9 function include cancers, cardiovasculardiseases, diseases in which angiogenesis or neovascularization play arole (neoplastic diseases, retinopathy and macular degeneration),infectious diseases (viral infections, e.g., HIV infection, andbacterial infections) and immunosuppressive diseases such as organtransplant conditions and skin transplant conditions. The term “organtransplant conditions” is means to include bone marrow transplantconditions and solid organ (e.g., kidney, liver, lung, heart, pancreasor combination thereof) transplant conditions.

Preferably, the present methods are directed to the treatment ofdiseases or conditions selected from inflammatory bowel diseaseincluding Crohn's disease and Ulcerative Colitis, allergic diseases,psoriasis, atopic dermatitis and asthma, autoimmune disease such asrheumatoid arthritis and immune-mediated food allergies such as Coelaicdisease.

Depending on the disease to be treated and the subject's condition, thecompounds and compositions of the present invention may be administeredby oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous,ICV, intracisternal injection or infusion, subcutaneous injection, orimplant), inhalation, nasal, vaginal, rectal, sublingual, or topicalroutes of administration and may be formulated, alone or together, insuitable dosage unit formulations containing conventional non toxicpharmaceutically acceptable carriers, adjuvants and vehicles appropriatefor each rouse of administration. The present invention alsocontemplates administration of the compounds and compositions of thepresent invention in a depot formulation.

In the treatment or prevention of conditions which require chemokinereceptor modulation an appropriate dosage level will generally be about0.001 to 100 mg per kg patient body weight per day which can beadministered in single or multiple doses. Preferably, the dosage levelwill be about 0.01 to about 25 mg/kg per day; more preferably about 0.05to about 10 mg/kg per day. A suitable dosage level may be about 0.01 to25 mg/kg per day, about 0.05 to 10 mg/kg per day, or about 0.1 to 5mg/kg per day. Within this range the dosage may be 0.005 to 0.05, 0.05to 0.5, 0.5 to 5.0, or 5.0 to 50 mg/kg per day. For oral administration,the compositions are preferably provided in the form of tabletscontaining 1.0 to 1000 milligrams of the active ingredient, particularly1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0,250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0milligrams of the active ingredient for the symptomatic adjustment ofthe dosage to the patient to be treated. The compounds may beadministered on a regimen of 1 to 4 times per day, preferably once ortwice per day.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, hereditary characteristics, generalhealth, sex, diet, mode and time of administration, rate of excretion,drug combination, the severity of the particular condition, and the hostundergoing therapy.

In still other embodiments, the present methods are directed to thetreatment of allergic diseases, wherein a compound or composition of theinvention is administered either alone or in combination with a secondtherapeutic agent, wherein said second therapeutic agent is anantihistamine. When used in combination, the practitioner can administera combination of the compound or composition of the present inventionand a second therapeutic agent. Also, the compound or composition andthe second therapeutic agent can be administered sequentially, in anyorder.

In yet other embodiments, the present methods are directed to thetreatment of psoriasis wherein a compound or composition of theinvention is used alone or in combination with a second therapeuticagent such as a corticosteroid, a lubricant, a keratolytic agent, avitamin D₃ derivative, PUVA and anthralin.

In other embodiments, the present methods are directed to the treatmentof atopic dermatitis using a compound or composition of the inventioneither alone or in combination with a second therapeutic agent such as alubricant and a corticosteroid.

In further embodiments, the present methods are directed to thetreatment of asthma using a compound or composition of the inventioneither alone or in combination with a second therapeutic agent such as aβ2-agonist and a corticosteroid.

The compounds and compositions of the present invention can be combinedwith other compounds and compositions having related utilities toprevent and treat the condition or disease of interest, such asinflammatory conditions and diseases, including inflammatory boweldisease, allergic diseases, psoriasis, atopic dermatitis and asthma, andthose pathologies noted above. Selection of the appropriate agents foruse in combination therapies can be made one of ordinary skill in theart. The combination of therapeutic agents may act synergistically toeffect the treatment or prevention of the various disorders. Using thisapproach, one may be able to achieve therapeutic efficacy with lowerdosages of each agent, thus reducing the potential for adverse sideeffects.

The weight ratio of the compound of the present invention to the secondactive ingredient may be varied and will depend upon the effective doseof each ingredient. Generally, an effective dose of each will be used.Thus, for example, when a compound of the present invention is combinedwith an NSAID the weight ratio of the compound of the present inventionto the NSAID will generally range from about 1000:1 to about 1:1000,preferably about 200:1 to about 1:200. Combinations of a compound of thepresent invention and other active ingredients will generally also bewithin the aforementioned range, but in each case, an effective dose ofeach active ingredient should be used.

EXAMPLES

Reagents and solvents used below can be obtained from commercial sourcessuch as Aldrich Chemical Co. (Milwaukee, Wis., USA). ¹H-NMR wererecorded on a Varian Mercury 400 MHz NMR spectrometer. Significant peaksare tabulated in the order: multiplicity (s, singlet; d, doublet; t,triplet; q, quartet; m, multiplet) and number of protons. Massspectrometry results are reported as the ratio of mass over charge,followed by the relative abundance of each ion (in parenthesis). Intables, a single m/e value is reported for the M+H (or, as noted, M−H)ion containing the most common atomic isotopes. Isotope patternscorrespond to the expected formula in all cases. Electrospray ionization(ESI) mass spectrometry analysis was conducted on a Hewlett-Packard MSDelectrospray mass spectrometer using the HP1100 HPLC for sampledelivery. Normally the analyte was dissolved in methanol at 0.1 mg/mLand 1 microlitre was infused with the delivery solvent into the massspectrometer, which scanned from 100 to 1500 daltons. All compoundscould be analyzed in the positive ESI mode, using acetonitrile/waterwith 1% formic acid as the delivery solvent. The compounds providedbelow could also be analyzed in the negative ESI mode, using 2 mM NH₄OAcin acetonitrile/water as delivery system.

Compounds within the scope of this invention can be synthesized asdescribed below, using a variety of reactions known to the skilledartisan. A sample of useful routes to both the benzophenone andheteroaryl derived subunits and to fully elaborated sulfonamidemolecules of formula (I) within this claim are provided below. In thedescriptions of the syntheses that follow, some precursors were obtainedfrom commercial sources. These commercial sources include AldrichChemical Co., Acros Organics, Ryan Scientific Incorporated, OakwoodProducts Incorporated, Lancaster Chemicals, Sigma Chemical Co.,Lancaster Chemical Co., TCI-America, Alfa Aesar, Davos Chemicals, andGFS Chemicals.

Compounds of the invention can be prepared using conventional syntheticmethodology. Examples of approaches that may be taken to synthesizethese compounds are shown below. Nonetheless, one skilled in the artwill recognize that alternative methods may be employed to synthesizethe target compounds of this invention, and that the approachesdescribed within the body of this document are not exhaustive, but doprovide broadly applicable and practical routes to compounds ofinterest.

Certain molecules claimed in this patent can exist in differentenantiomeric and diastereomeric forms and all such variants of thesecompounds are within the scope of the invention.

The detailed description of the experimental procedures used tosynthesize key compounds in this text lead to molecules that aredescribed by the physical data identifying them as well as by thestructural depictions associated with them.

Those skilled in the art will also recognize that during standard workup procedures in organic chemistry, acids and bases are frequently used.Salts of the parent compounds are sometimes produced, if they possessthe necessary intrinsic acidity or basicity, during the experimentalprocedures described within this patent.

Preparation of CCR9 Modulators

The following examples are offered to illustrate, but not to limit, theclaimed invention.

Additionally, those skilled in the art will recognize that the moleculesclaimed in this patent may be synthesized using a variety of standardorganic chemistry transformations.

Certain general reaction types employed widely to synthesize targetcompounds in this invention are summarized in the examples.Specifically, generic procedures for sulfonamide formation, pyridineN-oxide formation and 2-aminophenyl-arylmethanone synthesis viaFriedel-Crafts type approaches are given, but numerous other standardchemistries are described within and were employed routinely.

While not intended to be exhaustive, representative synthetic organictransformations which can be used to prepare compounds of the inventionare included below.

These representative transformations include; standard functional groupmanipulations; reduction such as nitro to amino; oxidations offunctional groups including alcohols and pyridines; aryl substitutionsvia IPSO or other mechanisms for the introduction of a variety of groupsincluding nitrile, methyl and halogen; protecting group introductionsand removals; Grignard formation and reaction with an electrophile;metal-mediated cross couplings including but not limited to Buckvald,Suzuki and Sonigashira reactions; halogenations and other electrophilicaromatic substitution reactions; diazonium salt formations and reactionsof these species; etherifications; cyclative condensations,dehydrations, oxidations and reductions leading to heteroaryl groups;aryl metallations and transmetallations and reaction of the ensuingaryl-metal species with an electrophile such as an acid chloride orWeinreb amide; amidations; esterifications; nuclephilic substitutionreactions; alkylations; acylations; sulfonamide formation;chlorosulfonylations; ester and related hydrolyses, and the like.

Example 1 General Procedure for the preparation ofN-Aryl-benzenesulfonamides

To the desired aniline (0.5 mmol) dissolved in pyridine and cooled in anice-water bath was added a solution of an aryl sulfonyl chloride (0.5mmol) dissolved in cold pyridine. The reaction mixture was then heatedto 60° C. with gentle shaking for 16 h. Evaporation of the solvent withstandard workup followed by either flash chromatography or reversedphase HPLC yielded the corresponding N-aryl-benzenesulfonamides.

Example 2 General Procedure for the Synthesis of(2-Amino-phenyl)-pyridinyl-methanones

To 12.5 mL 1 M BCl₃ (12 mmol, 1.2 eq.) in methylene chloride stirred at0° C. was added a solution of the desired haloaniline (10 mmol, 1.0 eq.)in 15 mL of TCE drop wise over 20 minutes. After 10 minutes the desiredcyanopyridine (11 mmol, 1.1 eq.) was added followed by AlCl₃ (15 mmol,1.5 eq.). The reaction was brought to RT, stirred for an hour thenheated at 80-90° C. until all of the DCM was distilled off. The reactionmixture was then refluxed at 160° C. for 4 hours, cooled to RT andstirred overnight. 10 mL 3 M HCl were carefully added and the mixturewas refluxed at 120° C. for 2-3 hours while reaction progress wasmonitored by LC/MS. The crude reaction was cooled to RT and 100 mL waterwere added. The crude mixture was extracted with DCM (2×50 mL), theaqueous layer was set aside and the organic layer was back extractedwith 50 mL 1 M HCl (aq.). All aqueous layers were combined, brought topH 12 with 3 M NaOH (aq.) and extracted with DCM (4×50 mL). The DCMlayer was dried on Na₂SO₄, filtered and concentrated by rotaryevaporation. The crude product was washed liberally with Et₂O and driedunder vacuum, and further purified by conventional techniques such ascolumn chromatography when necessary.

Example 3 General Procedure for the Synthesis of SulfonamidePyridine-N-Oxides

The desired N-Aryl-benzenesulfonamide (250 μmol) was dissolved in 2 mLDCM and m-CPBA (1.0-1.5 eq) was then added. The reaction was shaken atRT and monitored by LC-MS. Additional m-CPBA was added as needed inaliquots until the reaction was complete. In most cases the reactionrequired 15-24 h r×n time. Standard workup led to the isolation of crudeproducts, which were purified by column chromatography.

Example 4 Synthesis of (2-Amino-5-chloro-phenyl)-pyridin-4-yl-methanone

A solution of 4-chloroaniline (2.0 g, 16 mmol) in 30 mL of TCE was addeddrop wise to a solution of BCl₃ (1M in DCM) (24 ml, 24 mmol) with icebath cooling, over a period of 15 min and the reaction mixture stirredat that temperature for an additional 10 min. 4-Cyanopyridine (2.0 g, 19mmol) and AlCl₃ (3.0 g, 22 mmol) were added with ice-water cooling. Thesolution was allowed to warm to room temperature and stirred for 30 min.The resulting solution was refluxed at 160° C. for 4 h and stirred atroom temperature overnight. The reaction mixture was then treated with30 mL of 3N HCl and the mixture was refluxed at 110° C. for 1.5 h. Thereaction mixture was allowed to cool down to room temperature and thesolution was adjusted to pH12 with 6N NaOH and then diluted water andDCM. The resulting two layers were separated and the aqueous layer wasextracted with DCM three times and the organic layers combined and driedover sodium sulfate. After removal of the solvent, the resulting solidwas washed with ether to yield(2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone (2.8 g, 75%).

Example 5 Synthesis of(2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-2-yl)methanone

To 20 mL 1M BCl3 (20 mmol, 2.3 eq.) in DCM stirred at 0° C. was added asolution of 1.1 g 4-chloroaniline (8.6 mmol, 1.0 eq.) in 15 mL of TCEdrop wise over five minutes. After 10 minutes 1.1 g of2-cyano-6-methylpyridine (1.1 eq.) were added to the reaction mixtureand after 2 minutes 1.6 g AlCl₃ (12 mmol, 1.4 eq.) was added. After 5minutes the reaction was brought to RT, stirred for an hour then heatedat 160° C. for 17 hours. 100 mL 3M HCl were added and the reaction ismonitored by LC/MS. After 6 hours the reaction was removed from heat,cooled to RT and 300 mL water were added. The crude mixture wasextracted with DCM (1×500 mL), the aqueous layer was set aside and theorganic layer was back extracted with 300 mL 3M HCl (aq.). All aqueouslayers were combined, brought to pH 11 with 3M NaOH (aq.) and extractedwith DCM. The DCM layer was dried on Na₂SO₄, filtered and concentratedby rotary evaporation. Preparatory chromatography afforded the productas a cream colored solid which was converted to its HCl salt beforebeing characterized. ¹H NMR: δ (ppm): 2.83 (s, 3H), 7.32 (d, J=2.0 Hz,1H), 7.34 (d, J=1.6 Hz, 1H), 7.49 (d, J=7.6 Hz, 1H), 7.82-7.85 (m, 2H),7.99 (t, J=7.6 Hz, H), 8.27 (d, J=7.6 Hz, 1H), 10.83 (s, 1H). MS:(M+H)/z=247.0

Example 6 Synthesis of(5-chloro-2-nitro-phenyl)-(6-chloro-pyridin-3-yl)-methanol

A solution of 1.0 g 2-chloro-5-iodopyridine (4.1 mmol, 1.0 eq.) in 10 mLanhyd. THF was stirred at 40° C. to −50° C. After five minutes, 2.2 mLof 2.1 M ^(i)PrMgBr/THF (4.6 mmol, 1.1 eq.) were added drop wise over 1minute and the reaction mixture is maintained at −40 to −50° C. for 30minutes. 1.3 g 2-nitro-5-chlorobenzaldehyde (7.0 mmol, 1.7 eq.) was thenadded and the reaction was maintained at −50° C. After 1 hour, thereaction was allowed to warm to −10° C., and quenched with 50 mLsaturated brine after a further fifteen minutes. The crude product wasextracted with EtOAc, dried on Na₂SO₄ and concentrated by rotaryevaporation to yield desired product. MS: (M+H)/z=298.9

Example 7 Synthesis of(5-Chloro-2-nitro-phenyl)-(6-chloro-pyridin-3-yl)-methanone

To (5-Chloro-2-nitro-phenyl)-(6-chloro-pyridin-3-yl)-methanol was addedan excess (ca. 2 eq.) of PDC in DCM. The suspension was shaken at roomtemperature overnight. The reaction was monitored by LC-MS, another 1-2eq. of PDC was added and the reaction was shaken for another 6 hours.The crude product was filtered through Celite and purified by flashchromatography (silica gel, DCM). ¹H NMR (CDCl₃): δ (ppm): 7.50 (d,J=2.4 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.68 & 7.70 (dd, J=8.8 Hz, 2.0Hz, 1H), 8.09-8.11 (m, 1H), 8.24 (d, J=8.8 Hz, 1H), 8.57 (d, J=2.0 Hz, 1H. MS: (M+H)/z=296.9

Example 8 Synthesis of(2-Amino-5-chloro-phenyl)-(6-chloro-pyridin-3-yl)-methanone

3-(5-chloro-2-nitrophenyl)-pyridinylmethanone was added to a mixture ofconcentrated HCl, DMF, SnCl₂ and heated at 130° C. The reaction wasmonitored by LC/MS and removed from heat after 2 h. The crude reactionwas treated with aq. K₂CO₃, extracted into DCM and concentrated byrotary evaporation. The crude product was purified by preparatorychromatography. MS: (M+H)/z=267.0

Example 9 Synthesis of N-(4-Chloro-phenyl)-2,2-dimethyl-propionamide

To a solution of 4-chloroaniline (5.0 g, 39.2 mmol) in 25 mL pyridinewas added 5.3 mL (43.1 mmol) of pivaloyl chloride and the reactionmixture stirred overnight at room temperature. The mixture was pouredinto vigorously stirring 6M HCl, and the solids were collected by vacuumfiltration, washed well with H₂O, and dried in vacuo to yield the titlecompound. ¹H NMR (CDCl3) δ 7.47 (d, J=9.2 Hz, 2H) 7.30 (s, 1H) 7.27 (d,J=8.8 Hz, 2H) 1.32 (s, 9H) MS (ES) m/z=212.1

Example 10 Synthesis ofN-[4-chloro-2-(hydroxy-pyridin-3-yl-methyl)-phenyl]-2,2-dimethyl-propionamide

N-(4-Chloro-phenyl)-2,2-dimethyl-propionamide (3.0, 14.2 mmol) wasdissolved in 15 mL THF in a dry 100 mL flask fitted with a rubber septaand nitrogen inlet and cooled to 0° C. in ice water bath for 25 minutes.A solution of 2.5M BuLi in hexane (17.0 mL, 42.6 mmol) was added and themixture stirred for 45 minutes. To the thick yellow precipitate thatformed was added a solution of pyridine-3-carboxaldehyde (3.03 g, 28.4mmol) in 15 mL THF. The ice bath was removed and the mixture was allowedto stir at room temperature for 45 minutes and the reaction was quenchedwith 25 mL H₂O. The mixture was transferred to a separating funnel, andthe aqueous phase was discarded. The organics were dried in vacuo toyield product as an orange oil. ¹H NMR (CDCl3) δ 8.85 (m, 1H) 8.54 (m,1H) 8.42 (m, 1H) 8.10 (dd, J=8.8 Hz, 2.8 Hz, 1H) 7.50 (d, J=8.0 Hz, 1H)7.31 (m, 1H) 7.23 (m, 1H) 7.10 (m, 1H) 5.85 (m, 1H) 1.70 (d, 1H) 1.08(s, 9H); MS (ES) m/z=319.1 (MH)⁺

Example 11 Synthesis ofN-[4-chloro-2-(pyridine-3-carbonyl)-phenyl]-2,2-dimethyl-propionamide

N-[4-chloro-2-(hydroxy-pyridin-3-yl-methyl)-phenyl]-2,2-dimethyl-propionamide(1.0 g, 3.14 mmol) was dissolved in 5 mL pyridine and treated with CrO₃(0.75 g, 7.5 mmol, 2.39 eq). The mixture was stirred under N₂ at roomtemperature for five hours, diluted with 20 mL 1:2 EtOAc/H₂O, andfiltered through Celite. The aqueous phase was separated and discarded,then the organics dried under vacuum yielding product (680 mg, 70%). ¹HNMR (CDCl₃) δ 11.06 (s, 1H) 8.92 (d, J=2.4 Hz, 1H) 8.84 (d, J=8.0 Hz,1H) 8.73 (d, J=9.2 Hz, 1H) 8.00 (d, J=8.0 Hz, 1H) 7.56 (dd, J=11.2 Hz,2.0 Hz, 1H) 7.48 (m, 2H) 1.36 (s, 9H) MS (ES) m/z=317.1 (MH)⁺

Example 12 Synthesis of (2-amino-5-chloro-phenyl)-pyridin-3-yl-methanone

N-[4-chloro-2-(pyridine-3-carbonyl)-phenyl]-2,2-dimethyl-propionamide(0.65 g) was suspended in 5 mL of 70% H₂SO₄ and heated at 95° C. in oilbath overnight. After cooling to room temperature the solution was addeddrop wise with stirring to 20 mL of 40% NaOH solution placed in anice-water bath. The fine yellow precipitate formed was collected byvacuum filtration, washed well with water and dried under vacuum to give370 mg of product. ¹H NMR (CDCl3) δ 8.84 (dd, J=2.4 Hz, 0.8 Hz, 1H) 8.77(dd, J=4.8 Hz, 2.0 Hz, 1H) 7.93 (dt, J=8.4 Hz, 2.0 Hz, 1H) 7.43 (m, 1H)7.35 (d, J=2.0 Hz, 1H) 7.25 (d, J=0.8 Hz, 1H) 6.71 (d, J=8.8 Hz, 1H)6.21 (s, 2H) MS (ES) m/z=233.0 (MH)⁺

Example 13 Synthesis of 2-methyl-isonicotinonitrile

Dimethyl sulfate (18.3 mL, 192.4 mmol) was added to stirring2-picoline-N-oxide (20 g) over a 10 minute period. The reaction wasexothermic and the material quickly became homogeneous. The mixture washeated in a 60° C. oil bath for 2 hours, then the volatiles were removedunder vacuum and the pale yellow oil was diluted with 25 mL H₂O andadded drop wise over 10 minutes to 160 mL of 25% (w/v) KCN/H₂O. Afterstirring for 3.5 hours the yellow precipitate formed was collected byvacuum filtration and purified by column chromatography (EtOAc/Hexane)to yield 13.0 g of product (60%). ¹H NMR (CDCl3) δ 8.66 (d, J=4.8 Hz,1H) 7.37 (s, 1H) 7.31 (d, J=4.4 Hz, 1H) 2.62 (s, 3H) 2.62 (s, 3H); MS(ES) m/z=119.0

Example 14 Synthesis of(2-amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone

The title compound was prepared according to the general procedure forthe Synthesis of (2-Amino-phenyl)-aryl-methanones, using4-chloro-phenylamine (1.8 g, 14.2 mmol) and 2-methyl-isonicotinonitrile(2.0 g, 16.9 mmol). ¹H NMR (CDCl3) δ 8.64 (d, J=4.8 Hz, 1H) 7.28 (m, 3H)7.20 (d, J=6.0 Hz, 1H) 6.70 (d, J=12.4 Hz, 1H) 6.28 (s, 2H) 2.66 (s, 3H)MS (ES) m/z=247.0

Example 15 Synthesis of (2-amino-5-chloro-phenyl)-pyridin-2-yl-methanone

To a solution of 2-bromopyridine (5 ml, 52 mmol) in Et₂O (60 ml) wasadded 40 ml of a n-butyllithium (1.6M in hexane, 64 mmol) drop wise at−40° C. over 30 min under a nitrogen atmosphere. The resulting yellowsolution was stirred for a further 1 hr at −50° C. to −30° C. In aseparate flask, a solution of 2-amino-5-chlorobenzoic acid (2.05 g, 12mmol) in dry THF (90 ml), under nitrogen atmosphere and withice-cooling, was added in one portion to the solution prepared asdescribed above. The reaction mixture was stirred for 2 hrs at 0° C. andthen chlorotrimethylsilane (30 ml) was added at 0° C. with stirring. Thereaction mixture was allowed to warm to room temperature and 1 N HCl aq(100 ml) was added. The resulting two-phase system was separated. Theaqueous phase was adjusted to pH12 with 6N NaOH solution and extractedwith ethyl acetate (2×150 ml). The combined organic extractions weredried over Na₂SO₄. After removal of solvent, the residue was purified bythe flash chromatography using ethyl acetate/hexane (1:4) as eluent.Crystallization of the product from Et₂O/hexane mixture gave 1.26 g(45%) of desired product as yellow solid. ¹H-NMR (DMSO-d₆, 500 MHz): δ6.90 (1H, d, J=9 Hz), 7.31 (1H, dd, J=9 and 2.5 Hz), 7.40 (2H, br), 7.53(1H, d, J=2.5 Hz), 7.61 (1H, m), 7.79 (1H, d, J=8 Hz), 8.03 (1H, m),8.69 (1H, m). MS: (ESI⁺): 233.2 (M+1).

Example 16 Synthesis of(2-Amino-5-chloro-phenyl)-(3-methyl-pyridin-4-yl)-methanone

To a solution of 3-picoline (50 g, 0.48 mol) in glacial acetic acid (150ml) was added hydrogen peroxide (25 ml) at RT. The mixture was heated to90° C. for 3 hr. The mixture was cooled to RT and more hydrogen peroxide(18.5 ml) was added slowly. The mixture was again heated to 90° C. for19 hr. The excess peroxide was carefully decomposed using Pd—C (2.5 g)at 0° C. Pd—C was removed by filtration, and the filtrate wasconcentrated and crude 3-methylpyridine-1-oxide was purified byfractional distillation in vacuo.

A solution of 3-methylpyridine-1-oxide (10 g, 0.092 mol) in methyliodide (15 ml) was left at rt for 18 hr and the solid was filtered. Thefiltrate was diluted with diethyl ether and extracted with water (40ml). The solid was re-dissolved in the aqueous extract, 1,4-dioxane (50ml) was added, followed by potassium cyanide (15 g, 0.23 mol) and themixture was stirred at RT for 3 hr. The product was extracted withchloroform. The chloroform layer was washed with water, brine and driedover sodium sulfate. The solvent was removed in vacuo and the crudeproduct was purified by fractional distillation (61-62° C./0.2 mm) toyield a white low melting solid.

BCl₃ (24 ml, 1M in DCM, 0.024 mol) was added slowly to a solution of4-chloroaniline (2 g, 0.016 mol) in 30 ml of trichloroethylene over aperiod of 15 min. at 0° C. and stirred at this temperature for anadditional 10 min. 4-Cyano-3-methylpyridine (2.2 g, 0.019 mol) and AlCl₃(3 g, 0.022 mol) were added at 0° C. The solution was allowed to warm toRT and stirred for 30 min. The solution was then heated at 80-90° C. for1 hr. and the DCM was distilled off. The resulting solution was refluxedat 115° C. for 4 hr and stirred at RT overnight. 3N HCl (20 ml) wasadded and the mixture refluxed at 100° C. for 2 hr. The reaction mixturewas cooled to 0° C. and adjusted to pH-12 with 6N NaOH. The reactionmixture was extracted with DCM., and the DCM layer washed with water,brine and dried over Na₂SO₄. The solvent was removed, and the crude waspurified by column chromatography over silica gel to yield a yellowsolid.

Example 17 Synthesis of(2-Amino-4,5-difluoro-phenyl)-pyridin-4-yl-methanone

Iron powder (28.1 g, 0.502 mol) was added as small portions to1,2-difluoro nitrobenzene (20.0 g, 0.126 mol) in methanol (200 ml) andheated to 60° C. Ammonium chloride (48.4 g, 0.91 mol) in water (100 ml)was added drop wise and the reaction mixture refluxed for 5 hr. Thereaction mixture was filtered over Celite and washed with methanol.Methanol was removed, and the aqueous layer was extracted withethylacetate, washed with brine, dried over sodium sulphate andconcentrated to yield 1,2-difluoro-4-aminobenzene (7 g, 43%).

BCl₃ (6.2 ml, 1M in DCM) was added drop wise to1,2-difluoro-4-aminobenzene (0.5 g, 0.004 mol) in trichloroethylene (6.5ml) at 0° C. and this mixture stirred for 15 min. 4-Cyanopyridine (0.48g, 0.005 mol) was added and the solution was warmed to RT and stirredfor 30 min. The solution was then heated at 80-90° C. for 1 h. Theresulting solution was refluxed at 160° C. for 4 hr and stirred at RTover night. 3N HCl was added to the reaction mixture and refluxed at110° C. for 1.5 h. The reaction mixture was cooled to RT and made basic(pH=12) with 6N NaOH. The reaction mixture was diluted with water andDCM. The resulting two layers were separated and the aqueous layer wasextracted with DCM, dried over sodium sulphate and concentrated. Thecompound was purified by column chromatography using silica gel to yieldtitle compound (0.25 g, 27%).

Example 18 Synthesis of(6-Amino-2,3-difluoro-phenyl)-pyridin-4-yl-methanone

To 3,4-Difluoroaniline (2.0 g, 0.0153 mol) and triethylamine (3.1 g,0.0307 mol) in dry benzene (100 ml) was added trimethylacetylchloride(2.3 g, 0.0184 mol) slowly at 0° C. and the reaction mixture stirred atRT overnight. The reaction mixture was then quenched with water andextracted with ethyl acetate. The organic layer was washed with water,brine, dried over sodium sulfate and concentrated. Compound wasrecrystallized from petroleum ether yielding 3.2 g, 98%.

This protected 3,4-difluoroaniline (2.7 g, 0.0126 mol) was taken in dryTHF (25 ml) and under nitrogen t-butyllithium (2.02 g, 0.032 mol) wasadded drop wise at −78° C. Stirring was continued at −78° C. for 2 h.4-Pyridine carboxaldehyde (3.55 g, 0.033 mol) dissolved in dry THF (10ml) was added slowly. The reaction mixture was warmed to roomtemperature and stirred over night. The reaction mixture was thenquenched with water and extracted with ether. The organic layer waswashed with brine, dried over sodium sulfate and concentrated. Compoundwas purified by column chromatography to yield carbinol (2.6 g, 65%).

To carbinol (2.6 g, 0.0031 mol) in 17.3 ml of pyridine was added asuspension of chromium trioxide (0.705 g, 0.007 mol) in pyridine (6.0ml) under a nitrogen atmosphere. The resulting mixture was allowed tostir at RT over night. The reaction mixture was poured into water andextracted with ether. The ether extract was washed with brine, driedover sodium sulfate and concentrated. The compound was purified bycolumn chromatography to yield the protected precursor to the titlecompound (1.7 g, 65.8%).

To this pivaloyl protected amino ketone (1.7 g, 0.0053 mol) was added70% sulfuric acid (14.6 ml) and the reaction mixture heated to 95-100°C. overnight. The reaction mixture was basified by using 10% sodiumhydroxide and extracted with dichloromethane. The organic layer waswashed with water, brine, dried over sodium sulfate and concentrated.The product obtained was purified by column chromatography to yieldtitle compound (0.58 g, 46.4%).

Example 19 Synthesis of(2-Amino-5-chloro-4-methoxy-phenyl)-pyridin-4-yl-methanone

5-Nitro-2-chloro aniline (50.0 g, 0.289 mol) in 30% sulfuric acid (300ml) was stirred at RT for 2 h. Sodium nitrite (21.0 g, 0.304 mol) inwater (50 ml) was added slowly at 0° C. After 15 mins, this solution wasadded slowly to dilute sulfuric acid (50%, 250 ml) at 110° C. Stirringwas continued for 15 min. The reaction mixture was cooled to RT, icewater was added, extracted with ethylacetate, washed with water, brineand dried over Na₂SO₄. The phenol product obtained upon concentrationwas purified by column chromatography. Yield 12.0 g, 24.0%.

K₂CO₃ (23.84 g, 0.172 mol) was added to 2-chloro-5-nitrophenol (10.0 g,0.058 mol) in acetonitrile (100 ml) at RT. After cooling to 0° C.,methyl iodide (19.6 g, 0.138 mol) was added slowly and the reactionmixture stirred at RT overnight. Water (100 ml) was added and theaqueous layer extracted with ethyl acetate. The organic layer was washedwith water, brine and dried over Na₂SO₄. The product obtained uponconcentration was purified by column chromatography to yield the anisole(6.0 g, 55.55%).

2-Chloro-5-nitro anisole (6.0 g, 0.032 mol) in MeOH (45 ml) was addedslowly to stannous chloride (15.1 g, 0.08 mol) in conc. HCl (110 ml) at40° C. and the temperature was slowly raised to 50° C. Stirring wascontinued for 2 h. After cooling to RT, the reaction mixture wasbasified with 50% NaOH solution, extracted by ethyl acetate, washed withwater, then brine and dried over Na₂SO₄. 3-Methoxy-4-chloroaniline wasobtained upon concentration and was purified further by columnchromatography. Yield: 4.0 g, 79.36%.

To 3-Methoxy-4-chloroaniline (2.0 g, 0.0126 mol) in trichloroethylene(30 ml) was added BCl₃ (2.18 g, 1 M solution in DCM, 0.0188 mol) at 0°C. After stirring for 10 min, 4-cyanopyridine (1.6 g, 0.0153 mol) andAlCl₃ (2.35 g, 0.018 mol) were added and the temperature was raised toRT, with further stirring for 30 min. The temperature was raised furtherto 85° C. and maintained at the same temperature for 1 h. DCM wasdistilled off and the solution was stirred at 115° C. for 4 h and thenat RT over night. 3N HCl was added at RT and the reaction mixturerefluxed for 1.5 h. The reaction mixture was allowed to cool and madebasic using NaOH (6 N), diluted with water and extracted with DCM,washed with water, brine and dried over Na₂SO₄. The crude title compoundwas obtained upon concentration and was purified by columnchromatography. Yield: 0.50 g, 15

Example 20 Synthesis of(2-Amino-5-chloro-phenyl)-pyrimidin-4-yl-methanone

To 4-Methyl pyrimidine (5.0 g, 0.053 mol) in pyridine (55 ml) was addedselenium dioxide (8.82 g, 0.079 mol) at RT with stirring. The reactionmixture was stirred at 55° C. for 2 h and at 80° C. for 3.5 hr. Aftercooling to RT and stirring over night, the reaction mixture was filteredand the residue was washed with pyridine. The combined pyridine solutionwas concentrated and the carboxylic acid obtained was washed with waterto remove traces of selenium dioxide. Yield: 5.3 g, 80.5%.

To Pyrimidine-4-carboxylic acid (5.0 g, 0.04 mol) in methanol (170 ml)was added conc. HCl (2 ml) at RT. After refluxing overnight, thereaction mixture was cooled to RT and neutralized with 10% sodiumbicarbonate solution and concentrated. The ester was extracted withdiethyl ether, dried over Na₂SO₄ and concentrated to get the methylester as a yellow solid, yield: 3.3 g, 57.55%.

Trimethyl acetylchloride (11.30 g, 0.093 mol) was added to a benzene(500 ml) solution of triethylamine (15.75 g, 0.155 mol) and4-chloroaniline (10.0 g, 0.078 mol) at 0° C. The reaction mixture waswarmed to RT and stirred for 3 h. The reaction mixture was then quenchedwith water, extracted with ethyl acetate, washed with water, brinesolution and dried over Na₂SO₄. The solid product obtained wascrystallized from pet ether. Yield: 14.0 g, 84.43%.

To N-(4-chlorophenyl)-2,2-dimethyl propanamide (3.5 g, 0.0165 mol) inTHF (50 ml) at 0° C. was added n-butyl lithium in hexane (2.64 g, 1.2 M,0.041 mol). Stirring was continued at 0° C. for 2 h, the reaction thencooled to −70° C., pyrimidine-4-methyl carboxylate (3.18 g, 0.023 mol)in THF (25 ml) was then added slowly and the solution was warmed to RTand stirred overnight. Diethyl ether (50 ml) and water (50 ml) wereadded and the organic layer was separated. The aqueous layer was furtherextracted with ether. The combined ether layers were washed with water,brine and dried over Na₂SO₄. The product obtained upon concentration waspurified by column chromatography. Yield: 1.7 g, 32.69%.

The protected amino ketone (1.7 g, 0.0054 mol) in sulfuric acid (10 ml,70%) was heated at 95° C. over night. The reaction mixture was cooled toRT and basified with 10% NaOH, extracted with DCM, washed with water,brine and dried over Na₂SO₄. The product obtained upon concentration waspurified by column chromatography using basic alumina to yield titlecompound (0.20 g, 16%).

Example 21 Synthesis of(6-Amino-3-chloro-2-methoxy-phenyl)-pyridin-4-yl-methanone

5-Nitro-2-chloro aniline (50.0 g, 0.289 mol) in 30% sulfuric acid (300ml) was stirred at RT for 2 h. Sodium nitrite (21.0 g, 0.304 mol) inwater (50 ml) was added slowly at 0° C. and maintained at thistemperature for 15 min. This diazotized solution was added slowly todilute sulfuric acid (50%, 250 ml) at 110° C. Stirring was continued for15 min. After cooling to RT, ice water was added, the mixture extractedwith ethylacetate, washed with water, brine and dried over Na₂SO₄. Theproduct obtained upon concentration was purified by columnchromatography. Yield 12.0 g, 24.0%.

To K₂CO₃ (23.84 g, 0.172 mol) and 2-chloro-5-nitrophenol (10.0 g, 0.0576mol) in acetonitrile (100 ml) was added methyl iodide (19.60 g, 0.138mol) at 0° C. The reaction mixture was warmed to RT and stirredovernight. Water was added and extracted with ethyl acetate. The organiclayer was washed with water, brine and dried over Na₂SO₄. The productobtained upon concentration was purified by column chromatography.Yield: 6.0 g, 55.55%.

2-Chloro-5-nitro anisole (6.0 g, 0.032 mol) in MeOH (45 ml) was addedslowly to stannous chloride (15.1 g, 0.08 mol) in conc. HCl (110 ml) at40° C. and the temperature was slowly raised to 50° C. Stirring wascontinued for 2 h, the reaction cooled to RT, basified with 50% NaOHsolution and extracted by ethyl acetate. The organic layer was washedwith water, brine and dried over Na₂SO₄. The product obtained uponconcentration was purified by column chromatography. Yield: 4.0 g,79.36%.

To triethylamine (3.83 g, 0.037 mol) and 3-methoxy-4-chloro aniline (3.0g, 0.0190 mol) in benzene (50 ml) was added trimethylacetylchloride(2.75 g, 0.022 mol) slowly at 0° C. The temperature was raised to RT andstirred overnight. The reaction mixture was added to ice and extractedwith ethyl acetate. The organic layer was washed with water, brine,dried over Na₂SO₄ and concentrated. Yield: 3.7 g, 80.43%.

To N-pivaloyl-3-methoxy-4-chloroaniline (1.50 g, 0.0062 mol) in THF (30ml) was added n-butyl lithium (1.0 g, 0.0156 mol) at 0° C. and thereaction stirred for 2 hr. After cooling to −70° C., methylisonicotinate (1.3 g, 0.0094 mol) in THF (12 ml) was added slowly. Thereaction was warmed to rt and stirred overnight and then quenched withwater and extracted with ether. The water layer was further extractedand the combined ether layers were washed with water, brine and driedover Na₂SO₄. The product obtained upon concentration was purified bycolumn chromatography. Yield 0.50 g, 23.25%.

The protected ketone from step 5 (0.500 g, 0.0014 mol) was suspended inconcentrated HCl (5 ml) at RT, then the temperature was raised to 95° C.and the mixture stirred over night. The mixture was cooled to RT,basified with 20% NaOH solution and extracted with DCM. The combinedorganic layer was washed with water, brine and dried over Na₂SO₄. Theproduct obtained upon concentration was purified by columnchromatography using basic alumina to yield title compound (0.140 g,37.33%).

Example 22 Synthesis of(2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone

To a solution of 2-picoline (50 g, 0.48 mol) in glacial acetic acid (150ml) was added hydrogen peroxide (25 ml) at RT. The mixture was heated to90° C. for 3 hr. The mixture was cooled to RT and more hydrogen peroxide(18.5 ml) was added slowly. The mixture was again heated to 90° C. for19 hr. The excess peroxide was cautiously decomposed using Pd—C (2.5 g)at 0° C. Pd—C was filtered, the filtrate was concentrated and the crude2-methylpyridine-1-oxide was purified by fractional distillation undervacuum. Yield: 40 g, 69%.

A solution of 2-methylpyridine-1-oxide (10 g, 0.092 mol) in methyliodide (15 ml) was stirred at RT for 18 hr. The solid was filtered. Thefiltrate was diluted with diethyl ether, extracted with water (40 ml).The solid was re-dissolved in the aqueous layer, 1,4-dioxane (50 ml) wasadded, followed by potassium cyanide (15 g, 0.23 mol). The mixture wasstirred at RT for 3 hr. The product was extracted with chloroform. Thechloroform layer was washed with water, brine and dried over sodiumsulfate. The solvent was removed under vacuo and the crude material waspurified by fractional distillation (61-62° C./10.2 mm) to yield a whitelow melting solid (6 g, 35%).

BCl₃ (24 ml, 1M in DCM, 0.024 mol) was added slowly to a solution of4-chloroaniline (2 g, 0.016 mol) in 30 ml of trichloroethylene over aperiod of 15 min. at 0° C. and stirred at this temperature for anadditional 10 min. 4-Cyano-2-methylpyridine (2.2 g, 0.019 mol) and AlCl₃(3 g, 0.022 mol) were added at 0° C. The solution was warmed to RT andstirred for 30 min. The solution was then heated at 80-90° C. for 1 hand the DCM was distilled off. The resulting solution was refluxed at115° C. for 4 hr and stirred at RT over night. 3N HCl (20 ml) was addedto the mixture and refluxed at 100° C. for 2 hr. The reaction mixturewas cooled to 0° C. and was made basic (pH-12) with 6N NaOH and thereaction mixture was extracted with DCM. The DCM layer was washed withwater, brine and dried over Na₂SO₄. The solvent was removed, the crudewas purified by column chromatography (silica gel) to yield titlecompound as yellow solid (1.55 g, 40%).

Example 23 Synthesis of (2-Amino-4-chloro-phenyl)-pyridin-4-yl-methanone

To BCl₃(1M in DCM) (24 mL, 24 mmol), cooled to 0° C., a solution of3-chloroaniline (2.0 g, 16 mmol) in 30 mL of TCE was added drop wiseover a period of 15 min and the mixture stirred at that temperature foran additional 10 min. 4-cyanopyridine (2.0 g, 19 mmol) and AlCl3 (3.0 g,22 mmol) was added under ice-water cooling. The solution was allowed towarm to rt and stirred for 30 min. The solution was then heated at80-90° C. for 1 h and the DCM distilled off. The resulting solution wasrefluxed at 160° C. for 4 h and stirred at rt overnight. 3N HCl (20 mlapprox.) was added to the reaction mixture and then refluxed at 110° C.for 1.5 hr. The reaction mixture was cooled to rt and the solution wasmade basic (pH 12) with 6N NaOH. The reaction mixture was diluted withwater and DCM. The resulting two layers were separated and the aqueouslayer was extracted with DCM (3×150 mL), and dried (Na₂SO₄). Afterremoval of solvent, the solid was washed with Et₂O to give 650 mg (24%)of desired product.

Example 24 Synthesis of (2-Amino-3-chloro-phenyl)-pyridin-4-yl-methanone

To a solution of BCl₃(1M in DCM) (24 mL, 24 mmol), cooled to 0° C., wasadded a solution of 2-chloroaniline (2.0 g, 16 mmol) in 30 mL of TCEdrop wise over a period of 15 min and the reaction stirred for anadditional 10 min. 4-cyanopyridine (2.0 g, 19 mmol) and AlCl₃ (3.0 g, 22mmol) were added under ice-water cooling. The solution was allowed towarm to rt and stirred for 30 min. The solution was then heated at80-90° C. for 1 h and the DCM distilled off. The resulting solution wasrefluxed at 160° C. for 4 h and stirred at rt overnight. 3N HCl (20 mlapprox.) was added to the reaction mixture and refluxed at 110° C. for1.5 hr. The reaction mixture was cooled to rt and the solution was madebasic (pH 12) with 6N NaOH. The reaction mixture was diluted with waterand DCM. The resulting layers were separated and the aqueous layer wasextracted with DCM (3×150 mL), and the combined organic layers dried(Na₂SO₄). After removal of solvent, the solid was washed with Et₂O togive 600 mg (21%) of desired product.

Example 25 Synthesis of (2-Amino-5-bromo-phenyl)-pyridin-4-yl-methanone

To a solution of BCl₃ (1M in DCM) (18 mL, 18 mmol), cooled to 0° C., wasadded drop wise over a period of 15 min a solution of 4-bromoaniline (2g, 11.6 mmol) in 30 mL of TCE and the mixture stirred for an additional10 min. 4-cyanopyridine (2.0 g, 19 mmol) and AlCl3 (3.0 g, 22 mmol) wereadded under ice-water cooling. The solution was warmed to rt and stirredfor 30 min. The solution was then heated at 80-90° C. for 1 h and theDCM distilled off. The resulting solution was refluxed at 160° C. for 4h and stirred at rt overnight. 3N HCl (20 ml approx.) was added to thereaction mixture and refluxed at 110° C. for 1.5 hr. The reactionmixture was allowed to cool down and the solution was made basic (pH 12)with 6N NaOH. The reaction mixture was diluted with water and DCM. Theresulting two layers were separated and the aqueous layer was extractedwith DCM (3×150 mL), and the combined organic layers dried (Na₂SO₄).After removal of solvent, the solid was washed with Et₂O to give 1.050 gof desired product.

Example 26 Synthesis of (2-amino-5-fluoro-phenyl)-pyridin-4-methanone

To a solution of BCl3 (1M in DCM) (27 mL, 27 mmol), cooled to 0° C., wasadded drop wise over a period of 15 min a solution of 4-fluoroaniline(2.0 g, 18 mmol) in 30 mL of TCE and the mixture stirred at thattemperature for an additional 10 min. 4-cyanopyridine (2.6 g, 25 mmol)and AlCl3 (3.0 g, 22 mmol) were added under ice-water cooling. Thesolution was allowed to warm to rt and then stirred for 30 min. Thesolution was then heated at 80-90° C. for 1 h and the DCM distilled off.The resulting solution was refluxed at 160° C. for 4 h and stirred at rtovernight. 3N HCl (20 ml approx.) was added to the reaction mixture andrefluxed at 110° C. for 1.5 hr. The reaction mixture was allowed to cooldown and the solution was made basic (pH 12) with 6N NaOH. The reactionmixture was diluted with water and DCM. The resulting two layers wereseparated and the aqueous layer was extracted with DCM (3×150 mL), andthe combined organic layers dried (Na₂SO₄). After removal of solvent,the solid was washed with Et₂O to give 1.05 g (27%) of desired product.

Example 27 Synthesis of(2-Amino-5-chloro-phenyl)-(1-methyl-1H-imidazol-2-yl)-methanone

To a solution of nBuLi (0.0730 mol) in hexane was added N-methylimidazole (0.0608 mol) drop wise at −40° C. over 30 min under a nitrogenatmosphere. The resulting yellow solution was stirred for a further 3 hrat rt, and then refluxed for 1 h. 2-amino-5-chlorobenzoic acid (1.74 g,0.01014 mole) in dry ether (60 ml) was then added to the reactionmixture. The reaction mixture was stirred overnight at rt. To thereaction mixture was added saturated NH₄Cl solution and the resultingmixture extracted with ethyl acetate (2×150 ml). The combined organiclayers were dried over Na₂SO₄. After removal of solvent, the residue waspurified by the flash chromatography using ethyl acetate/hexane (1:4) aseluent. Crystallization of the product from Et₂O/hexane mixture gave 300mg (13.7%) of product as yellow solid.

Example 28 Synthesis of (2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-3-ylmethanone

Trimethylacetyl chloride (35 g) was added drop wise to a solution of4-chloroaniline (31.9 g) in dry pyridine and the reaction was stirredunder nitrogen overnight. About half of the pyridine was removed byrotary evaporation, then the mixture was treated with 6M hydrochloricacid and extracted with ethyl acetate. The extracts were washed withsaturated aqueous NaHCO3 and with water, then were dried (MgSO4),filtered and concentrated by rotary evaporation. The resultingcrystalline product was vacuum filtered and dried at high vacuum toconstant weight, resulting in a good yield ofN-(4-chloro-phenyl)-2,2-dimethyl-propionamide as fine needles. EDC (10g) and 2-methyl-nicotinic acid (7.15 g) were magnetically stirred inacetonitrile-THF with N,O-dimethylhydroxylamine hydrochloride (9.75 g)and triethylamine (25 mL). After stirring overnight at ambienttemperature, the resulting white suspension was added to ice water andextracted with ethyl acetate (3×100 mL). The extracts were dried,filtered, and concentrated to give a light amber oil.

To a magnetically stirred solution ofN-(4-chloro-phenyl)-2,2-dimethyl-propionamide (3.16 g, 14.9 mmol) in dryTHF was added 2.5M n-butyllithium in hexane at −40° C. and the mixturewas stirred at 0° C. for 2 h and a suspension of white solid resulted. Asolution of the Weinreb amide (1.80 g, 10.0 mmol) in dry THF was addeddrop wise and the reaction was stirred at ambient temp overnight. Themixture was diluted with water and extracted with ethyl acetate and theorganic layer was dried (MgSO₄), filtered and concentrated.Chromatography on silica gel (20-30% EtOAc/Hexane) provided the desiredN-[4-Chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-2,2-dimethyl-propionamideas a waxy bright yellow solid (2.28 g, 6.89 mmol): ¹H NMR (CDCl3) δ11.71 (s, 1H, NH), 8.82 (d, 1H, J=9.2 Hz), 8.67 (dd, 1H, J=4.8 Hz, J=1.8Hz), 7.55 (m, 2H), 7.28 (d, 1H, J=2.5 Hz), 7.25 (m, 1H), 2.54 (s, 3H),1.39 (s, 9H).

TheN-[4-chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-2,2-dimethyl-propionamideintermediate (2.28 g, 6.89 mmol) was magnetically stirred with 70%sulfuric acid and heated at 75° C. and progress of the solvolysis wasmonitored by LC/MS. The reaction was allowed to cool to ambienttemperature, and was washed with ether-hexane to remove oilyby-products. The acidic aqueous layer was cooled in an ice bath andaqueous NaOH was added drop wise to basify the mixture. The product wasextracted with ethyl acetate and the extracts were washed with saturatedaqueous NaHCO3 (2×100 mL), with saturated aqueous sodium chloride, dried(MgSO4), filtered and concentrated. The bright yellow productcrystallized on standing: ¹H NMR (CDCl3) δ 8.54 (dd, 1H, J=5.2 Hz, J=1.6Hz), 7.45 (dd, 1H, J=7.6 Hz, J=1.5 Hz), 7.15 (m, 2H), 7.00 (d, 1H, J=2.6Hz), 6.61 (d, 1H, J=9.1 Hz), 6.39 (br s, 2H), 2.42 (s, 3H).

Example 29 Synthesis of(2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone

The title compound was prepared using procedures described above for thesynthesis of 2-amino-5-chloro-phenyl)-(2-methyl-pyridin-3-yl)-methanone.

Example 30 Synthesis ofN-[4-Chloro-2-pyridine-4-carbonyl)-phenyl]-4-oxazol-5-yl-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using116-mg of (2-Amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 122 mg4-oxazol-5-yl-benzenesulfonyl chloride. Purification by purification byreversed phase HPLC gave pure product. ¹H-NMR (400 MHz, CDCl₃): δ 7.21(dd, H, J=1.5, 4.4 Hz), 7.30 (d, 1H, J=2.5 Hz), 7.42 (s, 1H), 7.54 (dd,1H, J=2.5, 8.8 Hz), 7.61 (d, 2H, J=8.4 Hz), 7.77 (s, 1H), 7.78 (d, 2H,J=8.4 Hz), 7.95 (s, 1H), 8.69 (d, 2H, J=5.8 Hz), 10.06 (br, 1H). MS: m/z440.9 (M⁺+1).

Example 31 Synthesis of4-tert-Butyl-N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using116 mg of (2-Amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 116 mg of4-tert-Butyl-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ 1.25(s, 9H), 7.02 (d, 1H, J=8.4 Hz). 7.44 (m, 3H), 7.66 (d, 2H, J=8.4), 7.79(d, 1H, J=2.4 Hz), 8.11 (d, 2H, J=6.4), 8.88 d, 2H, J=6.0 Hz), 10.51 (s,1H). MS: m/z 429.9 (M⁺+1).

Example 32 Synthesis of4-tert-Butyl-N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide

4-tert-Butyl-N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonamide(107 mg, 0.25 mmol) was dissolved in 4 mL DCM and m-chloroperoxybenzoic(0.26 mmol) was added. The mixture was stirred at room temperature for16 h. The solvent was evaporated on a rotary evaporator and the productwas purified by reversed phase HPLC to yield title compound. ¹H-NMR (400MHz, CDCl₃): δ 1.24 (s, 9H), 7.32-7.4 (m, 5H), 7.52 (dd, 1H, J=8.8, Hz,2.4 Hz), 7.63 (d, 2H, J=8.8 Hz), 7.74 (d, 1H, J=8.8 Hz), 8.18 (d, 2H,J=7.6 Hz), 9.60 (s, 1H). MS: m/z 445.9 (M⁺+1).

Example 33 Synthesis ofN-[4-Chloro-2-(pyridine-2-carbonyl)-phenyl]-4-methoxy-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using116 mg of (2-Amino-5-chloro-phenyl)-pyridin-2-yl-methanone and 101 mg of4-methoxy-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ 3.75 (s,3H), 6.76 (m, 2H, 7.45 (m, 2H), 7.63 (m, 2H), 7.71 (d, 1H, J=8.8 Hz),7.78 (m, 1H), 7.88 (m, 2H), 8.64 (m, 1H), 10.24 (s, 1H). MS: m/z 403.9(M⁺+1).

Example 34 Synthesis ofN-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-methoxy-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using116 mg of (2-Amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 101 mg of4-methoxy-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ 3.74 (s,3H), 6.77 (d, 2H, J=8.8 Hz), 7.21 (m, 2H), 7.27 (d, 1H, J=2 Hz), 7.52(dd, 1H, J=8.8 Hz, 2.8 Hz), 7.63 (m, 2H), 7.76 (d, 1H, J=8.8 Hz), 8.76(d, 2H, J=5.6 Hz), 9.88 (s, 1H). MS: m/z 403.9 (M⁺+1).

Example 35 Synthesis ofN-[4-Bromo-2-pyridine-4-carbonyl)-phenyl]-4-methoxy-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using138 mg of (2-amino-5-bromo-phenyl)-pyridin-4-yl-methanone and 101 mg of4-methoxy-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ 3.69 (s,3H), 6.68 (d, 2H, J=8.8 Hz), 7.36-7.47 (m, 4H), 7.46, 7.55-7.69 (m, 5H),9.65 (s, 1H). MS: m/z 448.3 (M⁺+1).

Example 36 Synthesis of4-tert-Butyl-N-[4-fluoro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using108 mg of (2-Amino-5-fluoro-phenyl)-pyridin-4-yl-methanone and 116 mg of4-tert-butyl-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ 1.25(s, 9H), 6.98 (dd, 1H, J=8.8 Hz, 3.2 Hz), 7.30-7.38 (m, 3H), 7.43 (m,2H), 7.62 (m, 2H), 7.80 (dd, 1H, 9.2 Hz, 4.8 Hz), 8.82 (d, 2H, 4.8 Hz),9.82 (s, 1H). MS: m/z 413.5 (M⁺+1).

Example 37 Synthesis ofN-[4-Bromo-2-(pyridine-4-carbonyl)-phenyl]-4-tert-butyl-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using138 mg of (2-Amino-5-bromo-phenyl)-pyridin-4-yl-methanone and 116 mg of4-tert-butyl-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ 1.27(3, 9H), 7.41 (m, 3H), 7.50 (dd, 2H, J=4.8 Hz, 1.6 Hz), 7.67-72 (m, 4H),8.85 (d, 2H, J=6 Hz), 10.19 (s, 1H). MS: m/z 473.9 (M⁺+1).

Example 38 Synthesis of4-tert-Butyl-N-[5-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using116 mg of (2-amino-4-chloro-phenyl)-pyridin-4-yl-methanone and 116 mg of4-tert-butyl-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ 1.30(s, 9H), 7.04 (d, 1H, J=8.4 Hz), 7.25 (d, 1H, J=8.4 Hz), 7.45-7.52 (m,4H), 7.74 (dd, 2H, J=8.8 Hz, 1.6 Hz), 7.52 (dd, 2H, J=4.4 Hz, 1.6 Hz),7.78 (m, 2H), 7.84 (d, 1.6 Hz), 8.84 (d, 2H, J=5.6 Hz), 10.61 (s, 1H).MS: m/z 429.0 (M⁺+1).

Example 39 Synthesis ofN-[4-Bromo-2-(pyridine-4-carbonyl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using138 mg of (2-Amino-5-bromo-phenyl)-pyridin-4-yl-methanone and 130 mg of4-trifluoromethoxy-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ7.21 (d, 2H, J=8.8 Hz), 7.35 (m, 2H), 7.45 (s, 1H), 7.70 (m, 2H), 7.83(m, 2H), 8.82 (dd, 2H, J=4.8 Hz, 1.6 Hz), 10.21 (s, 1H). MS: m/z 502.3(M⁺+1).

Example 40 Synthesis of4-Bromo-N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using116 mg of (2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 122 mg of4-bromo-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ 7.21 (d,1H, J=2.4 Hz), 7.49-7.61 (m, 5H), 7.73 (d, 1H, J=8.8 Hz), 8.86 (dd, 2H,J=4.4 Hz, 1.2 Hz), 10.00 (s, 1H). MS: m/z 451.9 (M⁺+1)

Example 41 Synthesis ofN-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-3-cyano-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using116 mg of (2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 100 mg of3-cyano-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ 7.36 (d,1H, J=2.4 Hz), 7.57-7.62 (m, 4H), 7.68 (d, 1H, J=8.8 Hz), 7.80 (m, 1H),8.04 (m, 2H), 8.90 (dd, 2H, J=4.8 Hz, 1.6 Hz), 10.3 (b, 1H). MS: m/z398.8 (M⁺+1).

Example 42 Synthesis ofN-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-methanesulfonyl-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using116 mg of (2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 127 mg of4-methanesulfonyl-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ3.06 (s, 3H), 7.31 (d, 1H, J=2.0 Hz), 7.45 (m, 2H), 7.58 (dd, 1H, J=8.8Hz, 2.8 Hz), 7.99 (b, 4H), 8.88 (dd, 2H, J=4.8 Hz, 1.6 Hz), 10.29 (b,1H). MS: m/z 451.9 (M⁺+1).

Example 43 Synthesis of4-tert-Butyl-N-[4-chloro-2-(pyrimidine-4-carbonyl)-phenyl]-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using116 mg of (2-Amino-5-chloro-phenyl)-pyrimidin-4-yl-methanone and 116 mgof 4-tert-butyl-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ1.23 (s, 9H), 7.40 (d, 2H, J=8.4 Hz), 7.51 (dd, 1H, J=8.8 Hz, 2 Hz),7.71-7.80 (m, 6H), 9.03 (d, 1H, J=4.8 Hz), 9.33 (d, 1.2 Hz), 10.91 (b,1H). MS: m/z 434.0 (M⁺+1).

Example 44 Synthesis of Biphenyl-4-sulfonicacid[4-chloro-2-pyridine-4-carbonyl)-phenyl]-amide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using116 mg of (2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 126 mg ofbiphenyl-4-sulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ 7.24 (m, 1H),7.36 (m, 2H), 7.42 (m, 5H), 7.56 (m, 3H), 7.77-7.84 (m, 3H), 8.73 (d,2H, J=4.4 Hz), 10.01 (s, 1H). MS: mm/z 449.0 (M⁺+1).

Example 45 Synthesis of4-tert-Butyl-N-[4-chloro-2-(3-methyl-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using123 mg of (2-Amino-5-chloro-phenyl)-(3-methyl-pyridin-4-yl)-methanoneand 116 mg of 4-tert-butyl-benzenesulfonyl chloride. ¹H-NMR (400 MHz,CDCl₃): δ 1.32 (s, 9H), 2.19 (s, 3H), 7.04 (d, 1H, J=1.4 Hz), 7.21 (d,1H, J=5.2 Hz), 7.48 (d, 2H, J=8.8 Hz), 7.52 (dd, 1H, J=8.8 Hz, 2.4 Hz),7.77-7.83 (m, 3H), 8.64 (d, 1H, J=5.2 Hz), 8.71 (s, 1H), 10.75 (s, 1H).MS: m/z 443.0 (M⁺+1).

Example 46 Synthesis ofN-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using116 mg of (2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 122 mg of4-Trifluoromethyl-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ7.31 (d, 1H, J=2.8 Hz), 7.36 (m, 2H), 7.54-7.59 (m, 2H), 7.73 (d, 1H,J=8.0 Hz), 7.77 (d, 1H, J=9.2 Hz), 7.97 (d, 1H, J=8.0 Hz), 8.00 (s, 1H),8.82 (dd, 2H, J=6.0 Hz, 1.2 Hz), 10.16 (s, 1H). MS: m/z 441.8 (M⁺+1).

Example 47 Synthesis of4-tert-Butyl-N-[4,5-difluoro-2-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using117 mg of (2-Amino-4,5-difluoro-phenyl)-pyridin-4-yl-methanone and 116mg of 4-tert-butyl-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ1.28 (s, 9H), 7.17 (t, 1H, J=8.4 Hz), 7.45 (d, 2H, J=8.4 Hz), 7.54 (d,2H, J=4.4 Hz), 7.64 (dd, 1H, J=11.6 Hz, 6.8 Hz), 7.72 (d, 2H, J=8.4 Hz),8.85 (d, 2H, J=5.2 Hz), 10.42 (s, 1H). MS: m/z 431.1 (M⁺+1).

Example 48 Synthesis of4-tert-Butyl-N-[4-chloro-2-(6-morpholin-4-yl-pyridine-3-carbonyl)-phenyl]-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using158 mg of(2-Amino-5-chloro-phenyl)-(6-morpholin-4-yl-pyridin-3-yl)-methanone and116 mg of 4-tert-butyl-benzenesulfonyl chloride. ¹H-NMR (400 MHz,CDCl₃): δ 1.22 (s, 3H), 3.76 (t, 4H, J=4.6 Hz), 3.857 (t, 4H, J=4.6H),8.78 (d, 1H, J=9.2 Hz), 7.30 (m, 2H), 7.34 (m, 1H), 7.46 (m, 1H),7.54-7.56 (m, 3H), 7.99 (d, 1H, J=9.2 Hz), 8.16 (v, 1H), 9.29 (s, 1H).MS: m/z 515.1 (M⁺+1).

Example 49 Synthesis ofN-[4-Chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-4-oxazol-5-yl-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using123 mg of (2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanoneand 122 mg of 4-oxazol-5-yl-benzenesulfonyl chloride. ¹H-NMR (400 MHz,CDCl₃): δ 2.63 (s, 3H), 7.33 (m, 2H), 7.37 (s, 1H), 7.56 (m, 3H),7.67-7.3 (m, 3H), 7.94 (m, 1H), 7.97 (s, 1H), 8.52 (b, 1H), 9.45 (s,1H). MS: m/z 454.1 (M⁺+1).

Example 50 Synthesis of4-tert-Butyl-N-[4-chloro-2-(2-methylsulfanyl-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide

4-tert-Butyl-N-[4-chloro-2-(2-chloro-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide(475 mg, 1.0 mmol) was dissolved in 10 mL dry THF and treated with solidsodium thiomethoxide (355 mg, 5 mmol) and the mixture heated at 70° C.for 16 h. The solvent was concentrated to about 2 mL and added to 5 mLcold 1M HCl. The light yellow solid precipitate was collected byfiltration and product was purified by HPLC. ¹H-NMR (400 MHz, CDCl₃): δ1.26 (s, 9H), 2.61 (s, 3H), 6.86 (d, 1H, J=5.2 Hz), 7.18 (s, 1H), 7.28(d, 1H, J=2.4 Hz), 7.39 (d, 2H, J=8.8 Hz), 7.51 (dd, 1H, J=8.8 Hz, 2.4Hz), 7.67 (m, 2H), 7.76 (d, 1H, J=8.8 Hz), 8.56 (d, 1H, J=5.2 Hz), 10.13(s, 1H). MS: m/z 476.1 (M⁺+1).

Example 51 Synthesis ofN-[4-Chloro-242-methyl-pyridine-4-carbonyl)-phenyl]-4-oxazol-5-yl-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using123 mg of (2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanoneand 122 mg of 4-oxazol-5-yl-benzenesulfonyl chloride. ¹H-NMR (400 MHz,CDCl₃): δ 2.78 (s, 3H), 7.29 (d, 1H, J=2.8 Hz), 7.45 (m, 2H), 7.48 (s,1H), 7.55 (dd, 1H, J=9.2 Hz, 2.8 Hz)), 7.67 (m, 3H), 7.83 (d, 2H, J=8.4Hz), 8.03 (s, 1H), 8.81 (d, 1H, J=5.6 Hz), 10.10 (s, 1H). MS: m/z 454.9(M⁺+1).

Example 52 Synthesis ofN-[4-Chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-4-(2-hydroxy-1,1-dimethylethyl)-benzenesulfonamide

To a suspension of NaBH₄ (0.70 g, 18.3 mmol) in dry THF (20 mL) wasadded BF₃.Et₂O (0.25 mL, 20.1 mmol) drop wise at 0° C. over 5 min andthe mixture was stirred for 30 min. A solution of2-methyl-2-phenyl-propionic acid (1.0 g, 6.1 mmol) in dry THF (10 mL)was added drop wise at 0° C. over 30 min, and the mixture was stirred atroom temperature for 4 h. Methanol was slowly added to the reactionmixture until hydrogen evolution stopped. The mixture was diluted with10% HCl and extracted twice with EtOAc. The organic layer was dried overNa₂SO₄ and then under vacuum to yield colorless oil.

This material was dissolved in DCM (25 mL), pyridine (1.2 mL, 15.3 mmol)and acetyl chloride (2.2 mL, 30.5 mmol) added, and the reaction mixtureleft to stir at room temperature overnight. The reaction mixture waswashed with 10% HCl and the organic layer was dried over MgSO₄.

The material was then dissolved in DCM (25 mL) and cooled to 0° C.Chlorosulfonic acid (1.2 mL, 18 mmol) was added drop wise over 15minutes and the mixture was stirred at the same temperature for 3H. Thevolatiles were evaporated and SOCl₂ (10 mL) was added and the mixturestirred at room temperature for 3 h. The excess SOCl₂ was evaporated andthe residue was treated with ice-water and extracted with ether. Theorganic layer was washed with water and brine, dried over MgSO₄ andconcentrated in vacuo to afford the aryl sulfonyl chloride as ayellowish oil.

This oil was treated with a solution of(2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone (1.2 g, 5 mmol) in 10mL pyridine and heated at 60 C for 4 h. The solvent was evaporated andthe residue suspended in 3M HCl (10 mL) and stirred at room temperaturefor 16 h. The reaction mixture was put in an ice bath and neutralizedwith concentrated NaOH solution. The white precipitate formed wascollected by filtration, washed with water and dried in vacuo andpurified by flash chromatography to yield 320 mg ofN-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide.

Oxidation of this intermediate with mCPBA according to the generalprocedure gaveN-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-4-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide.¹H-NMR (400 MHz, CDCl₃): δ 1.24 (s, 6H), 3.58 (s, 2H), 7.29 (d, 1H,J=2.4 Hz), 7.37 (m, 4H), 7.53 (m, 2H), 7.62 (m, 2H), 7.78 (d, 1H, J=8.8,Hz), 8.23 (d, 2H, J=6.8 Hz), 9.51 (s, 1H). MS: m/z 461.1 (M⁺+1).

Example 53 Synthesis ofN-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-4-ethyl-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using116 mg of (2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 102 mg of4-ethyl-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ 0.94 (t,3H, J=7.6 Hz), 2.38 (q, 2H, J=15.2 Hz, 7.6 Hz), 6.94 (d, 2H, J=6.8 Hz),7.16 (m, 2H), 7.23 (m, 1H), 7.30 (m, 4H), 8.60 (b, 2H), 9.73 (b, 1H).MS: m/z 401.1 (M⁺+1).

Example 54 Synthesis ofN-[4-Chloro-2-(pyrimidine-2-carbonyl)-phenyl]-4-oxazol-5-yl-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using116 mg of (2-Amino-5-chloro-phenyl)-pyrimidin-2-yl-methanone and 122 mgof 4-oxazol-5-yl-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ7.43 (s, 1H), 7.45 (m, 1H), 7.50 (m, 1H), 7.55 (m, 1H), 7.64 (m, 2H),7.66 (d, 1H, J=8.8 Hz), 7.86 (m, 2H), 7.97 (s, 1H), 8.86 (d, 2H), 10.63(s, 1H). MS: m/z 441.9 (M⁺+1).

Example 55 Synthesis ofN-[4-chloro-2-(pyrimidine-4-carbonyl)-phenyl]-4-oxazol-5-yl-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using116 mg of (2-Amino-5-chloro-phenyl)-pyrimidin-4-yl-methanone and 122 mgof 4-oxazol-5-yl-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ7.43 (s, 1H), 7.53 (dd, 1H, J=8.8 Hz, 2.4 Hz), 7.62 (m, 2H), 7.75 (m,2H), 7.80 (m, 3H), 7.98 (s, 1H), 8.99 (d, 1H, J=5.2 Hz), 9.25 (b, 1H),10.29 (b, 1H). MS: m/z 441.9 (M⁺+1).

Example 56 Synthesis ofN-[4-Chloro-2-(pyridine-3-carbonyl)-phenyl]-4-oxazol-5-yl-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using116 mg of (2-Amino-5-chloro-phenyl)-pyridin-3-yl-methanone and 122 mg of4-oxazol-5-yl-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ 7.23(m, 2H), 7.42-7.47 (m, 3H), 7.58-7.62 (m, 3H), 7.71 (dt, 1H, J=7.6 Hz,2.0 Hz), 7.88 (s, 1H), 8.45 (b, 1H), 8.58 (bd, 1H, J=3.6 Hz), 9.67 (s,1H). MS: m/z 458.1 (M⁺+1)

Example 57 Synthesis of4-tert-Butyl-N-[4-chloro-2-(pyridine-2-carbonyl)-phenyl]-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using116 mg of (2-Amino-5-chloro-phenyl)-pyridin-2-yl-methanone and 116 mg of4-tert-Butyl-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ 1.24(s, 9H), 7.34-7.38 (m, 2H), 7.47 (dd, 1H, J=8.8 Hz, 2.4 Hz), 7.60 (m,1H), 7.65-7.68 (m, 4H), 7.85 (d, 1H, J=8 Hz), 8.00 (td, 1H, J=7.6 Hz, 2Hz), 8.71 (bd, 1H, J=4.8 Hz). MS: m/z 429.9 (M⁺+1).

Example 58 Synthesis ofN-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-(1,1-dimethyl-propyl)-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using116 mg of (2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 123 mg of4-(1,1-dimethyl-propyl)-benzenesulfonyl chloride. ¹H-NMR (400 MHz,CDCl₃): δ 0.59 (t, 3H, J=7.2 Hz), 1.23 (s, 6H), 1.61 (q, 2H, J=7.2 Hz),7.28 (d, 1H, J=2.8 Hz), 7.36 (m, 2H), 7.53 (m, 3H), 7.67-7.74 (m, 3H),8.84 (m, 2H), 10.14 (s, 1H). MS: m/z 443.9 (M⁺+1).

Example 59 Synthesis of4-tert-butyl-N-[4-chloro-2-(2-chloro-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using133 mg of (2-Amino-5-chloro-phenyl)-(2-chloro-pyridin-4-yl)-methanoneand 116 mg of 4-tert-Butyl-benzenesulfonyl chloride. ¹H-NMR (400 MHz,CDCl₃): δ 1.26 (s, 9H), 7.18 (dd, 5.2 Hz, 1.6 Hz), 7.25 (m, 1H), 7.32(m, 1H), 7.41 (d, 2H, J=6.4 Hz), 7.54 (dd, 1H, J=9.2 Hz, 2.4 Hz), 7.67(m, 2H), 7.77 (d, 1H, J−8.8 Hz), 8.55 (d, 1H, J=5.2 Hz), 10.09 (s, 1H).MS: m/z 463.0 (M⁺+1).

Example 60 Synthesis ofN-[4-Chloro-2-(6-methyl-pyridine-2-carbonyl)-phenyl]-4-oxazol-5-yl-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using123 mg of (2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-2-yl)-methanoneand 122 mg of 4-oxazol-5-yl-benzenesulfonyl chloride ¹H-NMR (400 MHz,CDCl₃): δ 2.67 (s, 3H), 7.46-7.50 (m, 4H), 7.61-7.70 (m, 4H), 7.65 (m,2H), 7.94-8.00 (m, 1H), 8.15 (s, 1H). MS: m/z 454.0 (M⁺+1).

Example 61 Synthesis of4-tert-Butyl-N-[4-chloro-2-(2-methyl-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using123 mg of (2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanoneand 116 mg of 4-tert-Butyl-benzenesulfonyl chloride. ¹H-NMR (400 MHz,CDCl₃): δ 1.26 (s, 9H), 2.63 (s, 3H) 7.29 (d, 1H, J=2.8 Hz), 7.45-7.55(m, 3H), 7.67 (m, 2H), 7.83 (m, 2H), 8.03 (s, 1H), 8.81 (d, 1H, J=5.6Hz), 10.10 (s, 1H). MS: m/z 443.9 (M⁺+1).

Example 62 Synthesis4-tert-Butyl-N-[4-chloro-2-(2-methyl-1-oxy-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide

The title compound was prepared according to the general procedure bymCPBA oxidation of4-tert-butyl-N-[4-chloro-2-(2-methyl-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide.¹H-NMR (400 MHz, CDCl₃): δ 1.26 (s, 9H), 2.63 (s, 3H) 7.29 (d, 1H, J=2.8Hz), 7.50-7.57 (m, 3H), 7.67 (m, 2H), 7.87 (m, 2H), 8.24 (s, 1H), 8.89(d, 1H, J=5.6 Hz), 10.31 (s, 1H). MS: mm/z 459.0 (M⁺+1)

Example 63 Synthesis of4-tert-Butyl-N-[4-chloro-2-(6-methylsulfanyl-pyridine-3-carbonyl)-phenyl]-benzenesulfonamide

4-tert-Butyl-N-[4-chloro-2-(6-chloro-pyridine-3-carbonyl)-phenyl]-benzenesulfonamide(231 mg, 0.5 mmol) was dissolved in dry THF (5 mL) and treated withsodium thiomethoxide (175 mg, 2.5 mmol) and the mixture was heated at70° C. for 4 h. The solvent was evaporated and the residue suspended inwater (5 mL) and the product was precipitated by the drop wise additionof 3M HCl and purified by HPLC. ¹H-NMR (400 MHz, CDCl₃): δ 1.19 (s, 9H),2.60 (s, 3H), 7.21-7.28 (m, 3H), 7.31 (m, 1H), 7.50-7.54 (m, 3H), 7.65(dd, 1H, J=8.4 Hz, 2.4 Hz), 7.78 (d, 1H, J=8.8 Hz), 8.19 (m, 1H), 9.62(s, 1H). MS: m/z 476.0 (M⁺+1).

Example 64 Synthesis of4-tert-Butyl-N-[4-chloro-2-(6-methanesulfonyl-pyridine-3-carbonyl)-phenyl]-benzenesulfonamide

4-tert-Butyl-N-[4-chloro-2-(6-methylsulfanyl-pyridine-3-carbonyl)-phenyl]-benzenesulfonamide(48 mg, 0.1 mmol) and mCPBA (35 mg, 0.2 mmol) were dissolved in DCM (4mL) and the mixture stirred at room temperature overnight. The solventwas evaporated and product was purified by HPLC. ¹H-NMR (400 MHz,CDCl₃): δ1.25 (s, 9H), 3.30 (s, 3H), 7.27 (m, 1H), 7.38 (m, 2H), 7.56(dd, 1H, J=8.8 Hz, 2.8 Hz), 7.66 (m, 2H), 7.80 (d, 1H, J=8.8 Hz), 8.04(dd, 1H, J=8 Hz, 2 Hz), 8.18 (d, 1H, J=8.0 Hz), 8.61 (m, 1H), 10.00 (s,1H). MS: m/z 508.0 (M⁺+1).

Example 65 Synthesis of4-tert-Butyl-N-[3,4-difluoro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using117 mg of (6-Amino-2,3-difluoro-phenyl)-pyridin-4-yl-methanone and 116mg of 4-tert-Butyl-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ1.22 (s, 9H), 7.31 (d, 2H, J=8.4 Hz), 7.40-7.47 (m, 3H), 7.55 (d, 2H,J=8.4 Hz), 7.59 (m, 1H), 8.69 (b, 1H), 8.82 (d, 2H, J=6.0 Hz). MS: m/z431.0 (M⁺+1).

Example 66 Synthesis of4-tert-Butyl-N-[4-chloro-2-(pyrazine-2-carbonyl)-phenyl]-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using117 mg of (2-Amino-5-chloro-phenyl)-pyrazin-2-yl-methanone and 116 mg of4-tert-butyl-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ 1.24(s, 9H), 7.38 (dm, 2H, J=6.8 Hz), 7.50 (dd, 1H, J=9.2 Hz, 1.6 Hz), 7.70(m, 2H), 7.76 (m, 1H), 7.80 (m, 1H), 8.62 (m, 1H), 8.77 (m, 1H), 9.06(m, 1H), 10.37 (s, 1H). MS: m/z 430.0 (M⁺+1).

Example 67 Synthesis ofN-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-isopropoxy-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using116 mg of (2-Amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 117 mg of4-Isopropoxy-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ 1.01(d, 6H, J=5.6 Hz), 4.27 (m, 1H), 6.51 (d, 2H, J=8.8 Hz), 6.87 (d, 1H,J=8.8 Hz), 7.15-7.25 (m, 4H), 7.60 (d, 2H, J=6.0 Hz), 8.64 (d, 2H, J=6Hz), 9.60 (s, 1H). MS: m/z 431.9 (M⁺+1).

Example 68 Synthesis ofN-[4-Bromo-2-(pyridine-4-carbonyl)-phenyl]-4-isopropoxy-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using138 mg of (2-Amino-5-bromo-phenyl)-pyridin-4-yl-methanone and 117 mg of4-Isopropoxy-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ 1.31(d, 6H, J=6 Hz), 4.49 (q, 1H, J=6.0 Hz), 6.73 (d, 2H, J=6.8 Hz), 7.39(m, 3H), 7.63-7.70 (m, 4H), 8.82 (d, 2H, J=6.0 Hz), 9.99 (s, 1H). MS:m/z 476.0 (M⁺+1)

Example 69 Synthesis ofN-[4-Bromo-2-(pyridine-4-carbonyl)-phenyl]-4-ethyl-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using138 mg of (2-Amino-5-bromo-phenyl)-pyridin-4-yl-methanone and 102 mg of4-ethyl-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ1.19 (t, 3H,J=7.6 Hz), 2.62 (q, 2H, J=7.6 Hz), 7.20 (d, 2H, J=8.8 Hz, 7.38 (m, 3H),7.65-7.72 (m, 4H), 8.81 (d, 2H, 6.4 Hz), 10.06 (s, 1H). MS: m/z 446.0(M⁺+1).

Example 70 Synthesis ofN-[4-Bromo-2-(pyridine-4-carbonyl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using138 mg of (2-Amino-5-bromo-phenyl)-pyridin-4-yl-methanone and 130 mg of4-Trifluoromethoxy-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ7.23 (d, 2H, J=8.0 Hz), 7.45 (m, 3H), 7.71 (m, 2H), 7.85 (d, 2H, J=8.8Hz), 8.85 (d, 2H, J=6.4 Hz), 10.23 (s, 1H). MS: m/z 502.9 (M⁺+1).

Example 71 Synthesis of4-tert-Butyl-N-[4-chloro-2-(2-cyano-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide

Dimethyl sulfate (126 mg, 1 mmol) and4-tert-butyl-N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide(445 mg, 1 mmol) were dissolved in dry THF (5 mL). The reaction mixturewas stirred at room temperature for 1 hour and at 60° C. for two hours.After cooling to room temperature, to the solution was added 25% (w/v)aqueous KCN solution (5 mL) and the mixture stirred for 16 h. Thesolvent was evaporated in vacuo and the product was purified by HPLC.¹H-NMR (400 MHz, CDCl₃): δ 1.27 (s, 9H), 7.22 (d, 1H, J=2.0 Hz),7.41-7.47 (m, 3H), 7.56 (dd, 1H, J=2.4 Hz), 7.69 (m, 3H), 7.79 (d, 1H,J=9.2 Hz), 8.87 (d, 1H, J=5.2 Hz), 10.06 (s, 1H). MS: m/z 454.0 (M⁺+1).

Example 72 Synthesis of4-tert-Butyl-N-[4-chloro-2-(2-methanesulfonyl-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide

4-tert-Butyl-N-[4-chloro-2-(2-chloro-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide(232 mg, 0.5 mmol) was dissolved in dry THF (5 mL) and treated withsodium thiomethoxide (175 mg, 2.5 mmol) and the mixture was heated at70° C. for 16 h. The solvent was evaporated and the residue suspended inwater (5 mL) and the product was precipitated by the drop wise additionof 3M HCl. The precipitate was collected by filtration, dissolved in DCM(10 mL) and treated with mCPBA (172 mg, 1 mmol). After stirring at roomtemperature for 16 h, the DCM solution was washed with saturated NaHCO₃solution (10 mL). The organic layer was washed with water, dried and thesolvent was evaporated. The product was purified by HPLC to give whitepowder after lyophilization. ¹H-NMR (400 MHz, CDCl₃): δ 1.28 (s, 9H),3.30 (s, 3H), 7.24 (d, 1H, J=2.4 Hz), 7.45 (d, 2H, J=8.0 Hz), 7.48 (m,1H), 7.54 (dd, 1H, J=8.8 Hz, 2.4 Hz), 7.74 (d, 2H, J=8.0 Hz), 7.78 (d,1H, J=8.8 Hz), 8.87 (d, 1H, J=5.2 Hz), 10.23 (s, 1H). MS: m/z 507.0(M⁺+1).

Example 73 Synthesis ofN-[4-Bromo-2-(pyridine-4-carbonyl)-phenyl]-4-methanesulfonyl-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using138 mg of (2-Amino-5-bromo-phenyl)-phenyl-methanone and 127 mg of4-Methanesulfonyl-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ3.07 (s, 3H), 7.45 (d, 1H, J=2.0 Hz), 7.49 (d, 2H, J=6.0 Hz), 7.15 (m,3H), 8.00 (s, 4H), 8.89 (d, 2H, J=6.0 Hz), 10.32 (b, 1H). MS: m/z496.9.0 (M⁺+1).

Example 74 Synthesis of4-Acetyl-N-[4-bromo-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using138 mg of (2-Amino-5-bromo-phenyl)-phenyl-methanone and 109 mg of4-acetyl-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ 2.59 (s,3H), 7.44 (d, 1H, J=2.0 Hz), 7.56 (d, 2H, J=6.4 Hz, 7.64-7.71 (m, 2H),7.90 (d, 2H, J=8.8 Hz), 7.97 (d, 2H, J=8.8 Hz), 8.88 (d, 2H, J=6.4 Hz),10.24 (b, 1H). MS: m/z 459.8 (M⁺+1).

Example 75 Synthesis of4-tert-Butyl-N-[4-chloro-2-(6-methyl-pyridine-2-carbonyl)-phenyl]-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using(2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-2-yl)-methanone and4-tert-Butyl-benzenesulfonyl chloride and purified by HPLC. ¹H NMR: δ1.29 (s, 9H), 2.94 (s, 3H), 7.42-7.46 (m, 3H), 7.51 (d, J=8.8 Hz, 1H),7.58 (d, J=2.0 Hz, 1H), 7.62 (d. J=7.2 Hz, 1H), 7.66 (d, J=6.8 Hz, 1 H),7.74 (d, J=8.0 Hz, 1H), 8.1 (bs, 1H). MS: M/z 443.1 (M⁺+1).

Example 76 Synthesis of4-tert-Butyl-N-[4-chloro-2-(6-chloro-pyridine-3-carbonyl)-phenyl]-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using(2-Amino-5-chloro-phenyl)-(6-chloro-pyridin-3-yl)-methanone and4-tert-butyl-benzenesulfonyl chloride and purified by HPLC. ¹H NMR: δ1.21 (s, 9H), 7.30 (d, J=2.4 Hz, 1H), 7.33 (d, J=6.6 Hz, 2H), 7.43 (d,J=8.0 Hz, 1H), 7.52 & 7.55 (dd, J=8.8 Hz, 2.8 Hz, 1H), 7.60 (d, J=7.0Hz, 1H), 7.79 (m, 3H), 8.27 (d, J=2.0 Hz, 1H), 9.73 (s, 1H). MS: M/z463.0 (M⁺+1).

Example 77 Synthesis ofN-[4-Chloro-2-pyridine-3-carbonyl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using(2-amino-5-chlorophenyl)-pyridin-3-yl-methanone and4-Trifluoromethoxy-benzenesulfonyl chloride and purified by HPLC. ¹HNMR: δ 6.93 (d, J=8.0 Hz, 1H), 7.51 (d, J=8.8 Hz, 2H), 7.58-7.61 (m,3H), 7.67 (d, J=8.8 Hz, 2H), 8.03-8.05 (m, 1H), 8.74 (d, J=1.6 Hz, 1H),8.79 & 8.80 (dd, J=6.0 Hz, 1.6 Hz, 1H), 9.73 (s, 1H). MS: M/z 456.9(M⁺+1).

Example 78 Synthesis ofN-[4-Chloro-2-(pyridine-3-carbonyl)-phenyl]-4-methanesulfonyl-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using(2-amino-5-chloro-phenyl)-pyridin-3-yl-methanone and4-Methanesulfonyl-benzenesulfonyl chloride and purified by HPLC. ¹H NMR(CDCl₃): δ 3.01 (s, 3H), 7.36-7.37 (d, J=2.4 Hz, 1H), 7.43 (m, 1H), 7.54& 7.57 (dd, J=8.8 Hz, 2.4 Hz, 1H), 7.70-7.73 (m, 1H), 7.77 (d, J=8.8 Hz,1H), 7.90 (m, 4H), 8.59 (d, J=2.0 Hz, 1H), 8.80 & 8.82 (dd, J=4.8 Hz,1.6 Hz, 1H), 9.98 (s, 1H). MS: M/z 450.9 (M⁺+1).

Example 79 Synthesis ofN-[4-Chloro-2-pyridine-4-carbonyl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using(2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and4-Trifluoromethoxy-benzenesulfonyl chloride and purified by HPLC. ¹H NMR(DMSO-d6): δ 6.90 (d, J=8.4 Hz, 1H), 7.50 (d, J=8.8 Hz, 2H), 7.49-7.61(m, 4H), 7.66 (d, J=8.8 Hz, 2H), 8.81 (d, J=4.8 Hz, 2H), 10.26 (s, 1H).MS: M/z 456.9 (M⁺+1).

Example 80 Synthesis ofN-[4-Chloro-2-(pyridine-3-carbonyl)-phenyl]-4-isopropoxy-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using(2-amino-5-chloro-phenyl)-pyridin-3-yl-methanone and4-isopropoxy-benzenesulfonyl chloride and purified by HPLC. ¹H NMR(CDCl₃): δ 1.19 (s, 3H), 1.20 (s, 3H), 4.35-4.38 (m, 1H), 6.63 (d, J=9.2Hz, 2H), 7.24 (m, 2H), 7.35-7.38 (m, 1H), 7.43 (d, J=2.4 Hz, 1H),7.45-7.49 (m, 2H), 7.62 (d, J=8.8 Hz, 1H), 7.70-7.73 (m, 1H), 8.51 (bs,1H), 8.68 (bs, 1H), MS: M/z=431.0 (M⁺+1).

Example 81 Synthesis of4-Acetyl-N-[4-chloro-2-(1-oxy-pyridine-3-carbonyl)-phenyl]-benzenesulfonamide

The title compound was prepared by the mCPBA oxidation of4-Acetyl-N-[4-chloro-2-(pyridine-3-carbonyl)-phenyl]-benzenesulfonamideaccording to the general procedure.

Example 82 Synthesis ofN-[4-Chloro-2-(1-oxy-pyridine-3-carbonyl)-phenyl]-4-methanesulfonyl-benzenesulfonamide

The title compound was prepared by the mCPBA oxidation of4-methanesulfonyl-N-[4-chloro-2-(pyridine-3-carbonyl)-phenyl]-benzenesulfonamideaccording to the general procedure. ¹H NMR (DMSO-d6): δ 3.27 (s, 3H),6.90 (d, J=8.8 Hz, 1H), 7.47 & 7.49 (dd, J=8.0 Hz, 1.2 Hz, 1H),7.51-7.55 (m, 1H), 7.56 & 7.58 (dd, J=8.0 Hz, 2.4 Hz, 1H), 7.62 (d,J=2.0 Hz, 1H), 7.79 (d, J=7.6 Hz, 2H), 8.05 (d, J=8.8 Hz, 2H), 8.19 (d,J=2.0 Hz, 1H), 8.41 & 8.42 (dd, J=6.8 Hz, 1.2 Hz, 1H), 10.46 (s, 1H).MS: M/z 467.0 (M⁺+1).

Example 83 Synthesis of4-Chloro-N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using(2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and4-chloro-benzenesulfonyl chloride and purified by HPLC. ¹H NMR (CDCl₃):δ 7.20 (dd, 2H, J=4.4 Hz, 2H), 7.31 (m, 2H), 7.53 (dd, 1H, J=8.8 Hz, 2.8Hz), 7.65 (m, 2H), 7.76 (d, 1H, J=8.8 Hz), 8.79 (dd, 2H, J=4.4 Hz, 1.6Hz), 10.00 (s, 1H). MS: m/z 407.1 (M⁺+1).

Example 84 Synthesis of4-tert-Butyl-N-[4-chloro-2-(pyridine-3-carbonyl)-phenyl]-benzenesulfonamide

To (2-amino-5-chloro-phenyl)-pyridin-3-yl-methanone (150 mg, 0.64 mmol)dissolved in 750 uL pyridine was added 4-tert-butylbenzenesulfonylchloride (225 mg, 0.97 mmol) and the mixture stirred at 60° C.overnight. The reaction mixture was diluted with 1.0 mL H₂O and theprecipitate formed was collected by vacuum filtration. The crude productwas recrystallized from EtOAc/hexane yielding 190 mg of pure titlecompound. ¹H NMR (CDCl3) δ 9.87 (s, 1H), 8.79 (d, J=4.8 Hz, 1H), 8.52(s, 1H), 7.79 (d, J=8.8 Hz, 2H), 7.61 (d, J=8.8 Hz, 2H), 7.52 (dd, J=8.8Hz, 2.4 Hz, 1H), 7.40 (dd, J=7.6 Hz, 4.8 Hz, 1H), 7.33-7.31 (m, 3H),1.22 (s, 9H). MS: m/z=429.0 (M⁺+1).

Example 85 Synthesis of4-tert-Butyl-N-[4-chloro-2-(1-oxy-pyridine-3-carbonyl)-phenyl]-benzenesulfonamide

The title compound was prepared by the MCPBA oxidation of4-tert-Butyl-N-[4-chloro-2-(pyridine-3-carbonyl)-phenyl]-benzenesulfonamideaccording to the general procedure and purified by HPLC. ¹H NMR (CDCl3)δ 9.71 (s, 1H) 8.56 (d, J=7.6 Hz, 1H) 8.43 (s, 1H) 7.71-7.66 (m, 4H)7.61-7.53 (m, 2H) 7.44-7.38 (m, 3H) 1.28 (s, 9H). MS (ES) m/z=445.0(M⁺+1).

Example 86 Synthesis ofN-[4-Chloro-2-(2-methyl-pyridine-4-carbonyl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using(2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone and4-trifluoromethoxy-benzenesulfonyl chloride and purified by HPLC. ¹H NMR(CDCl3) δ 10.17 (s, 1H) 8.63 (d, J=4 Hz, 1H) 7.78 (m, 3H) 7.51 (s, 1H)7.30 (s, 1H) 7.17 (s, 1H) 7.09 (s, 1H) 6.97 (d, J=4 Hz, 2H) 2.64 (s,3H). MS (ES) m/z=471.0 (M⁺+1).

Example 87 Synthesis ofN-[4-Chloro-2-(2-methyl-pyridine-4-carbonyl)-phenyl]-4-isopropoxy-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using(2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone and4-isopropoxy-benzenesulfonyl chloride and purified by HPLC. ¹H NMR(CDCl3) δ 9.94 (s, 1H) 8.61 (d, J=5 Hz, 1H) 7.78 (d, J=8.8, 1H) 7.61 (d,J=8 Hz, 1H) 7.50 (dd, J=11 Hz, 2 Hz, 2H) 7.27 (d, J=2.4 Hz, 1H) 7.07 (s,1H) 6.96 (d, J=4 Hz, 1H) 6.75 (d, J=8.8 Hz, 2H) 4.47 (m, 1H) 2.63 (s,3H) 1.27 (s, 6H). MS (ES) m/z=445.0 (M⁺+1).

Example 88 Synthesis of4-Acetyl-N-[4-chloro-2-(2-methyl-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using(2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone and4-acetyl-benzenesulfonyl chloride and purified by HPLC. 1H NMR (CDCl3) δ8.50 (d, J=4.8 Hz, 1H) 7.67-7.25 (m, 5H) 7.20-6.85 (m, 4H) 2.52 (s, 3H)2.45 (s, 3H). MS: (ES) m/z=429.0 (M⁺+1).

Example 89 Synthesis ofN-[4-Chloro-2-(2-methyl-pyridine-4-carbonyl)-phenyl]-4-methanesulfonyl-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using(2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone and4-methanesulfonyl-benzenesulfonyl chloride and purified by HPLC. ¹H NMR(CDCl3) δ 10.38 (s, 1H) 8.64 (s 1H) 7.95 (s, 4H) 7.72 (s, 1H) 7.51 (s,1H) 7.31 (s, 1H) 7.11 (s, 1H) 6.99 (s, 1H) 3.04 (s, 3H) 2.64 (s, 3H).MS: (ES) m/z=464.9 (M⁺+1).

Example 90 Synthesis of3-{4-[4-Chloro-2-(2-methyl-pyridine-4-carbonyl)-phenylsulfamoyl]-phenyl}-propionicacid methyl ester

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using(2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone and3-(4-chlorosulfonyl-phenyl)-propionic acid methyl ester and purified byHPLC. ¹H NMR (CDCl3) δ 10.13 (s, 1H) 8.62 (d, J=4.8 Hz, 1H) 7.73 (d,J=8.8 Hz, 1H) 7.65 (d, J=8.8 Hz, 2H) 7.49 (dd, J=8.8 Hz, 2.4 Hz, 1H)7.28 (d, J=2.4 Hz, 1H) 7.19 (d, J=12 Hz, 2H) 7.13 (s, 1H) 6.95 (d, J=4.8Hz, 1H) 3.62 (s, 3H) 2.90 (t, J=8 Hz, 2H) 2.63 (s, 3H) 2.56 (t, J=8 Hz,2H). MS: m/z=473.0 (M⁺+1).

Example 91 Synthesis ofN-[4-Chloro-2-(2-methyl-1-oxy-pyridine-4-carbonyl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide

The title compound was prepared by the mCPBA oxidation ofN-[4-Chloro-2-(2-methyl-pyridine-4-carbonyl)-phenyl]-4-trifluoromethoxy-benzenesulfonamideaccording to the general procedure and purified by HPLC. ¹H NMR (CDCl3)δ 9.66 (s, 1H) 8.26 (d, J=6.8 Hz, 1H) 7.89 (d, 2H, J=8.4 Hz) 7.85 (s,1H) 7.81 (d, 2H, J=8.4 Hz) 7.73 (d, 1H, J=8.8 Hz) 7.54 (dd, 1H, J=12 Hz,2 Hz) 7.36 (t, 1H, J=5.6 Hz, 3.2 Hz) 7.24-7.19 (m, 1H) 2.55 (s, 3H). MS(ES) m/z=486.9 (M⁺+1).

Example 92 Synthesis ofN-[4-Chloro-2-(2-methyl-1-oxy-pyridine-4-carbonyl)-phenyl]-4-isopropoxy-benzenesulfonamide

The title compound was prepared by the mCPBA oxidation ofN-[4-Chloro-2-(2-methyl-pyridine-4-carbonyl)-phenyl]-4-isopropoxy-benzenesulfonamideaccording to the general procedure and purified by HPLC. ¹H NMR (CDCl3)δ 9.39 (s, 1H) 8.32 (d, J=6.8 Hz, 1H) 7.75 (d, J=11.2, 1H) 7.57-7.52 (m,3H) 7.36 (d, J=2.4 Hz, 1H) 7.30 (d, J=2.4 Hz, 1H) 7.21 (dd, J=7.2 Hz,2.8 Hz, 1H) 6.71 (d, J=7.2 Hz, 2H) 4.46 (p, J=6.0 Hz, 1H) 2.57 (s, 3H)1.29 (d, J=5.6 Hz, 6H). MS (ES) m/z=461.0 (M⁺+1).

Example 93 Synthesis ofN-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-iodo-benzenesulfonamide

To a magnetically stirred mixture of precursor amino-ketone (2.32 g,10.0 mmol) in dry pyridine (20 mL) was added a solution of pipsylchloride (4.78 g, 15.8 mmol) in toluene (20 mL) under dry nitrogen. Theaddition was performed over a 2 h period. The reaction was stirredovernight at 50° C., then additional pipsyl chloride (850 mg), as asolution in toluene, was added. After 6 h, the reaction was concentratedand the residue was taken up in ethyl acetate. The organic layer waswashed with water, then the mixture was filtered. The layers wereseparated and the organic layer was dried (MgSO₄), filtered andconcentrated to provide crystalline material. ¹H-NMR (CDCl3) δ 9.95 (brs, 1H, NH), 8.82 (dm, 2H, J=5.2 Hz), 7.76 (d, 1H, J=8.8 Hz), 7.54 (dm,1H, J=8.8 Hz, J=2.6 Hz), 7.41 (dm, 2H, J=8.8 Hz), 7.30 (d, 1H, J=2.6Hz), 7.30 (d, 1H, J=2.6 Hz), 7.19 (dm, 2H, J=5.2 Hz). MS: m/z 499 (M+1).

Example 94 Synthesis ofN-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-(2,4-dimethyl-oxazol-5-yl)-benzenesulfonamide

Trifluoromethanesulfonic acid (4.5 mmol) was added to a stirred solutionof iodobenzene diacetate (0.39 g, 1.2 mmol) in acetonitrile (10 mL) andstirred at ambient temperature for 20 minutes. To this reactionpropiophenone (1.0 mmol) was added and the reaction was refluxed for 2.5h. After completion of the reaction, as judged by TLC, excessacetonitrile was evaporated and the crude product was extracted intodichloromethane (3×40 mL). The combined organic extracts were thenwashed with saturated aqueous sodium bicarbonate (2×50 mL), dried(MgSO4), filtered and concentrated to give a dark amber waxy solid. Theproduct was purified by column chromatography on silica gel using ethylacetate-hexane (5:95, 10:90) to furnish a crystalline solid.

2,4-dimethyl-5-phenyloxazole (53 mg, 0.31 mmol) was treated withchlorosulfonic acid (3.0 equivalents) in dry dichloromethane (8 mL) at0° C. The solution was allowed to slowly warm to room temperature andmonitored by LC/MS for complete reaction, then the reaction was washedwith cold water. The organic layer was dried over magnesium sulfate,filtered and concentrated.

The residue was treated with thionyl chloride (2 equivalents) in drydichloromethane (5 mL). The desired product was isolated byconcentration of the reaction mixture to give4-(2,4-dimethyl-oxazol-5-yl)benzenesulfonyl chloride, which was usedimmediately in the next step: mass spectrum m/z 272 (M+1);

To a magnetically stirred solution of the aminoketone (1.62 g, 7.0 mmol)in dry pyridine (30 mL) was added drop wise a solution of the sulfonylchloride in 1.0 mL of dichloromethane and the slightly turbid reactionwas stirred at ambient temperature. After 5 h, the reaction was dilutedwith ethyl acetate (25 mL) and washed with cold 3M HCl, followed bywashing with aqueous NaHCO₃, then washed with water. The organic layerwas dried (MgSO4), filtered and concentrated to give a pale yellow waxysolid. The product was purified by preparative hplc and pure materiallyophilized to give the desired product. ¹H NMR (CDCl3) δ 8.84 (br s,2H), 7.69 (dm, 2H, J=8.4 Hz), 7.65 (d, 1H, J=8.8 Hz), 7.46 (dm, 1H,J=2.2 Hz), 7.43 (dm, 2H, J=8.4 Hz), 7.36 (ddd, 1H, J=8.8 Hz, J=2.6 Hz,J=0.7 Hz), 7.24 (2H, obscured), 7.15 (br s. 1H), 3.19 (s, 3H), 3.13 (s,3H). MS: m/z 468 (M+1).

Example 95 Synthesis of4-tert-Butyl-N-[4-chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using(2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-3-yl)-methanone (243 mg, 1.0mmol) and 4-tert-Butyl-benzenesulfonyl chloride (232 mg, 1.0 mmol) andpurified by HPLC. ¹H NMR (CDCl3) δ 10.71 (br s, 1H, NH), 8.63 (dd, 1H,J=5.1 Hz, J=1.6 Hz), 7.83 (d, 1H, J=8.8 Hz), 7.73 (dm, 2H, J=8.4 Hz),7.49 (dd, 1H, J=8.8 Hz, J=2.6 Hz), 7.43 (dm, 2H, J=8.5 Hz), 7.27 (dd,1H, J=9.5 Hz, J=1.8 Hz), 7.18 (dd, 1H, J=7.7 Hz, J=4.8 Hz), 7.13 (d, 1H,J=2.6 Hz), 2.29 (s, 3H), 1.29 (s, 9H). MS: m/z 443 (M+1).

Example 96 Synthesis of4-tert-Butyl-N-[4-chloro-2-(2-methyl-1-oxy-pyridine-3-carbonyl)-phenyl]-benzenesulfonamide

The title compound was prepared by the mCPBA oxidation of4-tert-Butyl-N-[4-chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-benzenesulfonamideaccording to the general procedure. ¹H NMR (CDCl₃) δ 10.71 (br s, 1H,NH), 8.62 (dm, 1H, J=5.9 Hz), 7.81 (d, 1H, J=9.1 Hz), 7.78 (dm, 2H,J=8.4 Hz), 7.54 (dd, 1H, J=8.8 Hz, J=2.6 Hz), 7.48 (dm, 2H, J=8.4 Hz),7.44 (m, 2H), 7.18 (d, 1H, J=2.6 Hz), 2.32 (s, 3H), 1.32 (s, 9H). MS:m/z 459 (M+1).

Example 97 Synthesis ofN-[4-Chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-4-isopropoxy-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using(2-amino-5-chloro-phenyl)-(2-methyl-pyridin-3-yl)-methanone and4-isopropoxy-benzenesulfonyl chloride and purified by HPLC. ¹H NMR(CDCl₃) δ 10.63 (br s, 1H, NH), 8.63 (dd, 1H, J=4.8 Hz, J=1.8 Hz), 7.79(d, 1H, J=8.8 Hz), 7.71 (d, 1H, J=8.8 Hz), 7.48 (dd, 1H, J=9.0 Hz, J=2.2Hz), 7.27 (dd, 1H, J=7.7 Hz, J=1.8 Hz), 7.19 (dd, 1H, J=7.7 Hz, J=4.8Hz), 7.14 (d, 1H, J=2.2 Hz), 4.55 (septet, 1H, J=6 Hz), 2.35 (s, 3H),1.35 (d, 3H, J=6 Hz). MS: m/z 445 (M+1).

Example 98 Synthesis ofN-[4-Chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using(2 amino-5-chloro-phenyl)-(2-methyl-pyridin-3-yl)-methanone and4-trifluoromethoxy-benzenesulfonyl chloride and purified by HPLC.

¹H NMR (CDCl3) δ 10.76 (br s, 1H, NH), 8.65 (dd, 1H, J=4.8 Hz, J=2.0Hz), 7.88 (dm, 2H, J=8.8 Hz), 7.80 (d, H1, J=9.2 Hz), 7.52 (dd, 1H,J=9.0 Hz, J=2.2 Hz), 7.1-7.3 (m, 4H), 7.18 (d, 1H, J=2.6 Hz), 2.35 (s,3H). MS: m/z 471 (M+1).

Example 99 Synthesis of4-Acetyl-N-[4-chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using(2 amino-5-chlorophenyl)-(2-methyl-pyridin-3-yl)-methanone and4-acetyl-benzenesulfonyl chloride and purified by HPLC. ¹H NMR (CDCl3)δ10.79 (br s, 1H, NH), 8.65 (dd, 1H, J=4.8 Hz, J=1.8 Hz), 7.98 (d, 2H,J=8.8 Hz), 7.92 (d, 2H, J=8.8 Hz), 7.79 (d, 1H, J=9.2 Hz), 7.50 (dd, 1H,J=9.0 Hz, J=2.2 Hz), 7.22 (dd, 1H, J=7.7 Hz, J=1.5 Hz), 7.16 (m, 2H),2.60 (s, 3H), 2.36 (s, 3H). MS: m/z 429 (M+1).

Example 100 Synthesis ofN-[4-Chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-4-methanesulfonyl-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using(2 amino-5-chloro-phenyl)-(2-methyl-pyridin-3-yl)-methanone and4-methanesulfonyll-benzenesulfonyl chloride and purified by HPLC. ¹H NMR(CDCl3) δ 10.86 (br s, 1, NH), 8.65 (dd, 1H, J=4.8 Hz, J=1.8 Hz), 8.02(m, 4H), 7.78 (d, 1H, J=8.8 Hz), 7.53 (dd, 1H, J=8.8 Hz, J=2.6 Hz),7.1-7.3 (m, 3H), 3.07 (s, 3H), 2.41 (s, 3H). MS: m/z 465 (M+1).

Example 101 Synthesis of3-{4-[4-Chloro-2-(2-methyl-pyridine-3-carbonyl)-phenylsulfamoyl]-phenyl}-propionicacid methyl ester

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using(2 amino-5-chloro-phenyl)-(2-methyl-pyridin-3-yl)-methanone and3-(4-Chlorosulfonyl-phenyl)-propionic acid methyl ester and purified byHPLC. ¹H-NMR (CDCl3) δ 10.75 (br s, 1H, NH), 8.64 (dm, 1H, J=4.8 Hz),7.79 (dd, 1H, J=9.2 Hz, J=1.1 Hz), 7.75 (d, 2H, J=7.3 Hz), 7.49 (dm, 1H,J=9.2 Hz), 7.1-7.3 (m, 5H), 3.65 (s, 3H), 2.97 (t, 2H, J=7.6 Hz), 2.61(t, 2H, J=7.6 Hz), 2.35 (s, 3H). MS: m/z 473 (M+1).

Example 102 Synthesis ofN-[4-Chloro-2-(2-methyl-1-oxy-pyridine-3-carbonyl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide

The title compound was prepared by the mCPBA oxidation ofN-[4-Chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-4-trifluoromethoxy-benzenesulfonamideaccording to the general procedure. ¹H NMR (CDCl3) δ 10.68 (br s, 1H,NH), 8.54 (dm, 1H, J=6.6 Hz), 7.92 (dm, 2H, J=8.8 Hz), 7.78 (d, 1, J=8.8Hz), 7.56 (dd, 1, J=8.8 Hz, J=2.2 Hz), 7.45-7.15 (m, 4), 7.18 (d, 1,J=2.6 Hz), 2.33 (s, 3H). MS: m/z 487 (M+1).

Example 103 Synthesis ofN-[4-Chloro-2-(2-methyl-1-oxy-pyridine-3-carbonyl)-phenyl]-4-isopropoxy-benzenesulfonamide

The title compound was prepared by the mCPBA oxidation ofN-[4-chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-4-isopropoxy-benzenesulfonamideaccording to the general procedure. ¹H NMR (CDCl3) δ 10.56 (br s, 1H,NH), 8.56 (dm, 1H, J=6.6 Hz), 7.79 (d, 1H, J=8.8 Hz), 7.75 (d, 2H, J=8.8Hz), 7.53 (dd, 1H, J=8.8 Hz, J=2.6 Hz), 7.39 (t, 1H, J=7.2 Hz), 7.21 (d,1H, J=8.0 Hz), 7.17 (d, 1H, J=2.6 Hz), 6.87 (d, 2H, J=8.8 Hz), 4.58(septet, 1H, J=6 Hz), 2.32 (s, 3H), 1.35 (d, 3H, J=6 Hz). MS: m/z 461(M+1).

Example 104 Synthesis of4-Acetyl-N-[4-chloro-2-(2-methyl-1-oxy-pyridine-3-carbonyl)-phenyl]-benzenesulfonamide

The title compound was prepared by the mCPBA oxidation of4-Acetyl-N-[4-chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-benzenesulfonamideaccording to the general procedure. ¹H NMR (CDCl3) δ 10.7 (br s, 1H,NH), 8.54 (d, 1H, J=6.6 Hz), 8.02 (d, 2H, J=8.4 Hz), 7.95 (d, 2H, J=8.4Hz), 7.76 (d, 1H, J=8.8 Hz), 7.54 (dd, 1H, J=8.8 Hz, J=2.2 Hz), 7.38 (m,1H), 7.22 (d, 1H, J=2.6 Hz), 7.16 (dm, 1H, J=7.7 Hz), 2.62 (s, 3H), 2.33(s, 3H). MS: m/z 445 (M+1).

Example 105 Synthesis ofN-[4-Chloro-2-(2-methyl-1-oxy-pyridine-3-carbonyl)-phenyl]-4-methanesulfonyl-benzenesulfonamide

The title compound was prepared by the mCPBA oxidation ofN-[4-Chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-4-methanesulfonyl-benzenesulfonamideaccording to the general procedure. ¹H NMR (CDCl₃) δ 10.78 (br s, 1H,NH), 8.38 (dm, 1H, J=6.6 Hz), 8.05 (s, 4H), 7.76 (d, 1H, J=8.8 Hz), 7.55(dd, 1H, J=8.8 Hz, J=2.2 Hz), 7.25 (m, 1H), 7.22 (d, 1H, J=2.2 Hz), 6.76(dm, 1H, J=7.7 Hz), 3.09 (s, 3H), 2.32 (s, 3H). MS: m/z 481 (M+1).

Example 106 Synthesis of3-{4-[4-Chloro-2-(2-methyl-1-oxy-pyridine-3-carbonyl)-phenylsulfamoyl]-phenyl}-propionicacid methyl ester

The title compound was prepared by the mCPBA oxidation of3-{4-[4-Chloro-2-(2-methyl-pyridine-3-carbonyl)-phenylsulfamoyl]-phenyl}-propionicacid methyl ester according to the general procedure. ¹H NMR (CDCl3) δ10.66 (br s, 1H, NH), 8.54 (dm, 1H, J=6.2 Hz), 7.78 (m, 3H), 7.52 (dd,1H, J=8.8 Hz, J=2.2 Hz), 7.39 (t, 1H, J=7.2 Hz), 7.31 (d, 2H, J=8.0 Hz),7.18 (m, 2H), 3.65 (s, 3H), 2.99 (t, 2H, J=7.6 Hz), 2.64 (t, 2H, J=7.6Hz), 2.31 (s, 3H). MS: m/z 489 (M+1).

Example 107 Synthesis of4-tert-Butyl-N-[4-chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using(2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone and4-tert-butyl-benzenesulfonyl chloride and purified by HPLC. ¹H NMR(CDCl₃) δ 9.77 (br s, 1H, NH), 8.40 (dm, 1H, J=1.8 Hz), 7.77 (dm, 1H,J=8.6 Hz), 7.71 (dd, 1H, J=8.1 Hz, J=2.2 Hz), 7.58 (dm, 2H, J=8.6 Hz),7.50 (dd, 1H, J=9.0 Hz, J=2.4 Hz), 7.32 (d, 1H, J=2.2 Hz), 7.29 (dm, 2H,J=8.6 Hz), 7.23 (d, 1H, J=8.1 Hz), 2.63 (s, 3H), 1.20 (s, 9H). MS: m/z443 (M+1).

Example 108 Synthesis of4-tert-Butyl-N-[4-chloro-2-(6-methyl-1-oxy-pyridine-3-carbonyl)-phenyl]-benzenesulfonamide

The title compound was prepared by the mCPBA oxidation of4-tert-butyl-N-[4-chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-benzenesulfonamideaccording to the general procedure. ¹H NMR (CDCl₃) δ 9.64 (br s, 1H,NH), 8.47 (m, 1H), 7.68 (d, 1H, J=8.8 Hz), 7.66 (d, 2H, J=8.8 Hz), 7.64(m, 1H), 7.53 (m, 2H), 7.41 (d, 1H, J=2.2 Hz), 7.40 (d, 2H, J=8.8 Hz),2.69 (s, 3H), 1.26 (s, 9H). MS: m/z 459 (M+1).

Example 109 Synthesis ofN-[4-Chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using(2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone and4-trifluoromethyl-benzenesulfonyl chloride and purified by HPLC. ¹H-NMR(CDCl3) δ 9.76 (br s, 1, NH), 8.50 (d, 1H, J=2.2 Hz), 7.76 (d, 1H,J=8.8), 7.73 (d, 2H, J=9.2), 7.66 (dd, 1H, J=8.0, J=2.2), 7.54 (ddm, 1H,J=8.8 Hz, J=2.6 Hz), 7.37 (d, 1H, J=2.6), 7.24 (d, 1H, J=6 Hz), 7.10 (d,2H, J=8.8 Hz), 2.35 (s, 3). MS: m/z 471 (M+1).

Example 110 Synthesis ofN-[4-Chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-4-isopropoxy-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using(2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone and4-isopropoxy-benzenesulfonyl chloride and purified by HPLC. ¹H NMR(CDCl₃) δ 9.67 (br s, 1H, NH), 8.45 (d, 1H, J=1.8 Hz), 7.75 (d, 1H,J=8.8 Hz), 7.68 (dd, 1H, J=8.0 Hz, J=2.2 Hz), 7.55 (d, 2H, J=9.0 Hz),7.50 (dd, 1H, J=8.8 Hz, J=2.6 Hz), 7.32 (d, 1H, J=2.6 Hz), 7.24 (d, 1H,J=8.0 Hz), 6.68 (d, 2H, J=9.0 Hz), 4.43 (septet, 1H, J=6 Hz), 2.65 (s,3H), 1.28 (d, 3H, J=6 Hz). MS: m/z 445 (M+1).

Example 111 Synthesis of4-Acetyl-N-[4-chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using(2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone and4-acetyl-benzenesulfonyl chloride and purified by HPLC. ¹H NMR (CDCl₃) δ9.54 (br s, 1, NH), 8.30 (m, 1), 7.77 (d, 2, J=8.8 Hz), 7.71 (d, 2,J=8.8 Hz), 7.69 (m, 1), 7.54 (dd, 1, J=8.8 Hz, J=2.2 Hz), 7.33 (d, 1,J=2.2 Hz), 7.26 (m, 1), 7.21 (d, 1, J=8.0 Hz), 2.63 (s, 3), 2.52 (s, 3).MS: m/z 429 (M+1).

Example 112 Synthesis ofN-[4-Chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-4-methanesulfonyl-benzenesulfonamide

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using(2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone and4-Methanesulfonyl-benzenesulfonyl chloride and purified by HPLC. ¹H NMR(CDCl₃) δ 9.77 (br s, 1H, NH), 8.44 (dm, 1H, J=2.2 Hz), 7.87 (d, 2H,J=8.8 Hz), 7.83 (d, 2H, J=8.8 Hz), 7.76 (d, 1H, J=8.8 Hz), 7.60 (dd, 1H,J=8.0 Hz, J=2.2 Hz), 7.55 (dd, 1H, J=8.8 Hz, J=2.2 Hz), 7.36 (d, 1H,J=2.2), 7.26 (d, 1H, J=8.0 Hz), 3.00 (s, 3H), 2.66 (s, 3H). MS: m/z 465(M+1).

Example 113 Synthesis of3-{4-[4-Chloro-2(6-methyl-pyridine-3-carbonyl)-phenylsulfamoyl]-phenyl}-propionicacid methyl ester

The title compound was prepared according to the general procedure forthe synthesis of N-Aryl-benzenesulfonamides previously described using(2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone and3-(4-Chlorosulfonyl-phenyl)-propionic acid methyl ester and purified byHPLC. ¹H NMR (CDCl3) δ 9.66 (br s, 1H, NH), 8.34 (d, 1H, J=2.2 Hz), 7.75(d, 1H, J=8.8 Hz), 7.72 (d, 1H, J=8.0 Hz, J=2.2 Hz), 7.56 (d, 2H, J=8.4Hz), 7.51 (dd, 1H, J=8.8 Hz, J=2.2 Hz), 7.32 (d 1H, J=2.2 Hz), 7.26 (d,1H, J=7 Hz), 7.09 (d, 2H, J=8.4 Hz), 3.65 (s, 3H), 2.97 (t, 2H, J=7.6Hz), 2.66 (s, 3H), 2.51 (t, 2H, J=7.6 Hz). MS: m/z 473 (M+1).

Example 114 Synthesis ofN-[4-Chloro-2-(6-methyl-1-oxy-pyridine-3-carbonyl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide

The title compound was prepared by the mCPBA oxidation ofN-[4-Chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-4-trifluoromethoxy-benzenesulfonamideaccording to the general procedure. ¹H NMR (CDCl3) δ 9.60 (br s, 1, NH),8.42 (m, 1H), 7.78 (dm, 2H, J=8.4 Hz), 7.70 (dm, 1H, J=8.8 Hz), 7.56(dd, 1H, J=8.0 Hz, J=2.2 Hz), 7.44 (d, 1H, J=8.0 Hz), 7.41 (d, 1H, J=2.2Hz), 7.38 (dm, 1H, J=8.0 Hz), 7.20 (dm, 2H, J=8.4 Hz), 2.65 (s, 3H). MS:m/z 487 (M+1).

Example 115 Synthesis ofN-[4-Chloro-2-(6-methyl-1-oxy-pyridine-3-carbonyl)-phenyl]-4-isopropoxy-benzenesulfonamide

The title compound was prepared by the mCPBA oxidation ofN-[4-Chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-4-isopropoxy-benzenesulfonamideaccording to the general procedure. ¹H-NMR (CDCl₃) δ 9.53 (br s, 1H,NH), 8.25 (dm, 1H, J=1.5 Hz), 7.74 (d, 1H, J=8.8 Hz), 7.59 (dm, 2H,J=8.8 Hz), 7.52 (dd, 1H, J=8.8 Hz, J=2.6 Hz), 7.24 (d, 1H, J=8.0 Hz),7.33 (d, 1H, J=2.6 Hz), 7.20 (dd, 1H, J=8.0 Hz, J=1.6 Hz), 6.75 (dm, 2H,J=8.8 Hz), 4.51 (septet, 1H, J=6 Hz), 2.59 (s, 3H), 1.30 (d, 3H, J=6Hz). MS: m/z 461 (M+1).

Example 116 Synthesis of4-Acetyl-N-[4-chloro-2-(6-methyl-1-oxy-pyridine-3-carbonyl)-phenyl]-benzenesulfonamide

The title compound was prepared by the mCPBA oxidation of4-Acetyl-N-[4-chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-benzenesulfonamideaccording to the general procedure. ¹H-NMR (CDCl3) δ 9.16 (br s, 1H,NH), 8.15 (dm, 1H, J=2.0 Hz), 7.83 (d, 2H, J=8.1 Hz), 7.71 (d, 2H, J=8.1Hz), 7.71-7.67 (m, 2H), 7.58 (dd, 1H, J=8.8 Hz, J=2.2 Hz), 7.52 (d, 1H,J=8.4 Hz), 7.37 (d, 1H, J=2.2 Hz), 2.66 (s, 3H), 2.60 (s, 3H). MS: m/z445 (M+1).

Example 117 Synthesis ofN-[4-Chloro-2-(6-methyl-1-oxy-pyridine-3-carbonyl)-phenyl]-4-methanesulfonyl-benzenesulfonamide

The title compound was prepared by the mCPBA oxidation ofN-[4-Chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-4-methanesulfonyl-benzenesulfonamideaccording to the general procedure. ¹H-NMR (CDCl3) δ 9.39 (br s, 1H,NH), 8.61 (m, 1H), 7.88 (m, 4H), 7.68 (d, 1H, J=8.8 Hz), 7.60 (m, 2H),7.40 (m, 2H), 3.03 (s, 3H), 2.69 (s, 3H). m/z 481 (M+1)

Example 118 Synthesis of3-{4-[4-Chloro-2-(6-methyl-1-oxy-pyridine-3-carbonyl)-phenylsulfamoyl]-phenyl}-propionicacid methyl ester

The title compound was prepared by the mCPBA oxidation of3-{4-[4-Chloro-2-(6-methyl-pyridine-3-carbonyl)-phenylsulfamoyl]-phenyl}-propionicacid methyl ester according to the general procedure. ¹H-NMR (CDCl3) δ9.47 (br s, 1H, NH), 8.26 (m, 1H), 7.69 (d, 1H, J=8.8 Hz), 7.59 (dm, 2H,J=8.4 Hz), 7.53 (dd, 1H, J=8.8 Hz, J=2.6 Hz), 7.48 (m, 2H), 7.35 (d, 1H,J=2.6 Hz), 7.18 (dm, 2H, J=8.4 Hz), 3.64 (s, 3H), 2.88 (t, 2H, J=7.6Hz), 2.67 (s, 3H), 2.51 (t, 2H, J=7.6 Hz). MS: m/z 489 (M+1).

Measuring Efficacy of CCR9 Modulators In Vitro Assays

A variety of assays can be used to evaluate the compounds providedherein, including signaling assays, migration assays, and other assaysof cellular response. CCR9 receptor signaling assays can be used tomeasure the ability of a compound, such as a potential CCR9 antagonist,to block CCR9 ligand- (e.g. TECK)-induced signaling. A migration assaycan be used to measure the ability of a compound of interest, such as apossible CCR9 antagonist, to block CCR9-mediated cell migration invitro. The latter is believed to resemble chemokine-induced cellmigration in vivo.

In a suitable assay, a CCR9 protein (whether isolated or recombinant) isused which has at least one property, activity, or functionalcharacteristic of a mammalian CCR9 protein. The property can be abinding property (to, for example, a ligand or inhibitor), a signalingactivity (e.g., activation of a mammalian G protein, induction of rapidand transient increase in the concentration of cytosolic free calcium[Ca⁺⁺]), cellular response function (e.g., stimulation of chemotaxis orinflammatory mediator release by leukocytes), and the like.

The assay can be a cell based assay that utilizes cells stably ortransiently transfected with a vector or expression cassette having anucleic acid sequence which encodes the CCR9 receptor. The cells aremaintained under conditions appropriate for expression of the receptorand are contacted with a putative agent under conditions appropriate forbinding to occur. Binding can be detected using standard techniques. Forexample, the extent of binding can be determined relative to a suitablecontrol (for example, relative to background in the absence of aputative agent, or relative to a known ligand). Optionally, a cellularfraction, such as a membrane fraction, containing the receptor can beused in lieu of whole cells.

Detection of binding or complex formation can be detected directly orindirectly. For example, the putative agent can be labeled with asuitable label (e.g., fluorescent label, chemiluminescent label, isotopelabel, enzyme label, and the like) and binding can be determined bydetection of the label. Specific and/or competitive binding can beassessed by competition or displacement studies, using unlabeled agentor a ligand (e.g., TECK) as a competitor.

Binding inhibition assays can be used to evaluate the present compounds.In these assays, the compounds are evaluated as inhibitors of ligandbinding using, for example, TECK. In this embodiment, the CCR9 receptoris contacted with a ligand such as TECK and a measure of ligand bindingis made. The receptor is then contacted with a test agent in thepresence of a ligand (e.g., TECK) and a second measurement of binding ismade. A reduction in the extent of ligand binding is indicative ofinhibition of binding by the test agent. The binding inhibition assayscan be carried out using whole cells which express CCR9, or a membranefraction from cells which express CCR9.

The binding of a G protein coupled receptor by, for example, an agonist,can result in a signaling event by the receptor. Accordingly, signalingassays can also be used to evaluate the compounds of the presentinvention and induction of signaling function by an agent can bemonitored using any suitable method. For example, G protein activity,such as hydrolysis of GTP to GDP, or later signaling events triggered byreceptor binding can be assayed by known methods (see, for example,PCT/US97/15915; Neote, et al., Cell, 72:415425 (1993); Van Riper, etal., J. Exp. Med., 177:851-856 (1993) and Dahinden, et al., J. Exp.Med., 179:751-756 (1994)).

Chemotaxis assays can also be used to assess receptor function andevaluate the compounds provided herein. These assays are based on thefunctional migration of cells in vitro or in vivo induced by an agent,and can be used to assess the binding and/or effect on chemotaxis ofligands, inhibitors, or agonists. A variety of chemotaxis assays areknown in the art, and any suitable assay can be used to evaluate thecompounds of the present invention. Examples of suitable assays includethose described in PCT/US97/15915; Springer, et al., WO 94/20142; Bermanet al., Immunol. Invest., 17:625-677 (1988); and Kavanaugh et al., J.Immunol., 146:4149-4156 (1991)).

Calcium signaling assays measure calcium concentration over time,preferably before and after receptor binding. These assays can be usedto quantify the generation of a receptor signaling mediator, Ca⁺⁺,following receptor binding (or absence thereof). These assays are usefulin determining the ability of a compound, such as those of the presentinvention, to generate the receptor signaling mediator by binding to areceptor of interest. Also, these assays are useful in determining theability of a compound, such as those of the present invention, toinhibit generation of the receptor signaling mediator by interferingwith binding between a receptor of interest and a ligand.

In calcium signaling assays used to determine the ability of a compoundto interfere with binding between CCR9 and a known CCR9 ligand,CCR9-expressing cells (such as a T cell line MOLT-4 cells) are firstincubated with a compound of interest, such as a potential CCR9antagonist, at increasing concentrations. The cell number can be from10⁵ to 5×10⁵ cells per well in a 96-well microtiter plate. Theconcentration of the compound being tested may range from 0 to 100 uM.After a period of incubation (which can range from 5 to 60 minutes), thetreated cells are placed in a Fluorometric Imaging Plate Reader (FLIPR®)(available from Molecular Devices Corp., Sunnyvale, Calif.) according tothe manufacturer's instruction. The FLIPR system is well known to thoseskilled in the art as a standard method of performing assays. The cellsare then stimulated with an appropriate amount of the CCR9 ligand TECK(e.g. 5-100 nM final concentration) and the signal of intracellularcalcium increase (also called calcium flux) is recorded. The efficacy ofa compound as an inhibitor of binding between CCR9 and the ligand can becalculated as an IC50 (the concentration needed to cause 50% inhibitionin signaling) or IC90 (at 90% inhibition).

In vitro cell migration assays can be performed (but are not limited tothis format) using the 96-well microchamber (called ChemoTX™). TheChemoTX system is well known to those skilled in the art as a type ofchemotactic/cell migration instrument. In this assay, CCR9-expressingcells (such as MOLT-4) are first incubated with a compound of interest,such as a possible CCR9 antagonist, at increasing concentrations.Typically, fifty thousand cells per well are used, but the amount canrange from 10³-10⁶ cells per well. CCR9 ligand TECK, typically at 50 nM(but can range from 5-100 nM), is placed at the lower chamber and themigration apparatus is assembled. Twenty microliters of testcompound-treated cells are then placed onto the membrane. Migration isallowed to take place at 37 C for a period of time, typically 2.5 hours.At the end of the incubation, the number of cells that migrated acrossthe membrane into the lower chamber is then quantified. The efficacy ofa compound as an inhibitor of CCR9-mediated cell migration is calculatedas an IC50 (the concentration needed to reduce cell migration by 50%) orIC90 (for 90% inhibition).

In Vivo Efficacy Models for Human IBD

T cell infiltration into the small intestine and colon have been linkedto the pathogenesis of human inflammatory bowel diseases which includeCoeliac disease, Crohn's disease and ulcerative colitis. Blockingtrafficking of relevant T cell populations to the intestine is believedto be an effective approach to treat human IBD. CCR9 is expressed ongut-homing T cells in peripheral blood, elevated in patients with smallbowel inflammation such as Crohn's disease and Coeliac disease. CCR9ligand TECK is expressed in the small intestine. It is thus believedthat this ligand-receptor pair plays a role in IBD development bymediating migration of T cells to the intestine. Several animal modelsexist and can be used for evaluating compounds of interest, such aspotential CCR9 antagonists, for an ability to affect such T cellmigration and/or condition or disease, which might allow efficacypredictions of antagonists in humans.

Animal Models with Pathology Similar to Human Ulcerative Colitis

A murine model described by Panwala and coworkers (Panwala, et al., JImmunol., 161(10):5733-44 (1998)) involves genetic deletion of themurine multi-drug resistant gene (MDR). MDR knockout mice (MDR−/−) aresusceptible to developing a severe, spontaneous intestinal inflammationwhen maintained under specific pathogen-free facility conditions. Theintestinal inflammation seen in MDR−/− mice has a pathology similar tothat of human inflammatory bowel disease (IBD) and is defined by Th1type T cells infiltration into the lamina propria of the largeintestine.

Another murine model was described by Davidson et al., J Exp Med.,184(1):241-51 (1986). In this model, the murine IL-10 gene was deletedand mice rendered deficient in the production of interleukin 10(IL-10−/−). These mice develop a chronic inflammatory bowel disease(IBD) that predominates in the colon and shares histopathologicalfeatures with human IBD.

Another murine model for IBD has been described by Powrie et al., IntImmunol., 5(11):1461-71 (1993), in which a subset of CD4+ T cells(called CD45RB(high)) from immunocompetent mice are purified andadoptively transferred into immunodeficient mice (such as C.B-17 scidmice). The animal restored with the CD45RBhighCD4+ T cell populationdeveloped a lethal wasting disease with severe mononuclear cellinfiltrates in the colon, pathologically similar with human IBD.

Murine Models with Pathology Similar to Human Crohn's Disease

The TNF ARE(−/−) model. The role of TNF in Crohn's disease in human hasbeen demonstrated more recently by success of treatment using anti-TNFalpha antibody by Targan et al., N Engl J Med., 337(15):1029-35 (1997).Mice with aberrant production of TNF-alpha due to genetic alteration inthe TNF gene (ARE−/−) develop Crohn's-like inflammatory bowel diseases(see Kontoyiannis et al., Immunity, 10(3):387-98 (1999)).

The SAMP/yit model. This is model described by Kosiewicz et al., J ClinInvest., 107(6):695-702 (2001). The mouse strain, SAMP/Yit,spontaneously develops a chronic inflammation localized to the terminalileum. The resulting ileitis is characterized by massive infiltration ofactivated T lymphocytes into the lamina propria, and bears a remarkableresemblance to human Crohn's disease.

Example 119

This example illustrates the activity associated with representativecompounds of the invention.

Materials and Methods (In Vitro Assays) Reagents and Cells

MOLT-4 cells were obtained from the American Type Culture Collection(Manassas, Va.) and cultured in RPMI tissue culture medium supplementedwith 10% fetal calf serum (FCS) in a humidified 5% CO₂ incubator at 37°C. Recombinant human chemokine protein TECK was obtained from R&DSystems (Minneapolis, Minn.). ChemoTX® chemotaxis microchambers werepurchased from Neuro Probe (Gaithersburg, Md.). CyQUANT® cellproliferation kits were purchased from Molecular Probes (Eugene, Oreg.).Calcium indicator dye Fluo-4 AM was purchased from Molecular Devices(Mountain View, Calif.).

Conventional Migration Assay

Conventional migration assay was used to determine the efficacy ofpotential receptor antagonists in blocking migration mediated throughCCR9. This assay was routinely performed using the ChemoTX® microchambersystem with a 5-μm pore-sized polycarbonate membrane. To begin such anassay, MOLT-4 cells were harvested by centrifugation of cell suspensionat 1000 PRM on a GS-6R Beckman centrifuge. The cell pellet wasresuspended in chemotaxis buffer (HBSS with 0.1% BSA) at 5×10⁶ cells/mL.Test compounds at desired concentrations were prepared from 10 mM stocksolutions by serial dilutions in chemotaxis buffer. An equal volume ofcells and compounds were mixed and incubated at room temperature for 15minutes. Afterwards, 20 μL of the mixture was transferred onto the porusmembrane of a migration microchamber, with 29 μL of 50 nM chemokine TECKprotein placed at the lower chamber. Following a 150-minute incubationat 37° C., during which cells migrated against the chemokine gradient,the assay was terminated by removing the cell drops from atop thefilter. To quantify cells migrated across the membrane, 5 μL of 7×CyQUANT® solution was added to each well in the lower chamber, and thefluorescence signal measured on a Spectrafluor Plus fluorescence platereader (TECAN, Durham, N.C.). The degree of inhibition was determined bycomparing migration signals between compound-treated and untreatedcells. IC50 calculation was further performed by non-linear squaresregression analysis using Graphpad Prism (Graphpad Software, San Diego,Calif.).

RAM Assay

The primary screen to identify CCR9 antagonists was carried out usingRAM assay (WO 02101350), which detects potential hits by their abilityto activate cell migration under inhibitory TECK concentration. To beginsuch an assay, MOLT-4 cells were harvested by centrifugation of cellsuspension at 1000 RPM on a GS-6R Beckman centrifuge. The cell pelletwas resuspended in chemotaxis buffer (HBSS/0.1% BSA) at 5×10⁶ cells/mL.Twenty-five microliters of cells was mixed with an equal volume of atest compound diluted to 20 μM in the same buffer. Twenty microliters ofthe mixture was transferred onto the filter in the upper chemotaxischamber, with 29 μL of 500 nM chemokine protein TECK placed in the lowerchamber. Following a 150-minute incubation at 37° C., the assay wasterminated by removing the cell drops from atop the filter. To quantifycells migrated across the membrane, 5 μL of 7× CyQUANT® solution wasadded to each well in the lower chamber, and the fluorescence signalmeasured on a Spectrafluor Plus fluorescence plate reader (TECAN,Durham, N.C.).

For selection of potential hits, the level of migration activation wascalculated as a RAM index-the ratio between the signal of a particularwell and the median signal of the whole plate. Compounds with a RAMindex of greater than 1.8 were regarded as RAM positive, and wereselected for IC50 determinations in conventional functional assays.

Calcium Flux Assay

Calcium flux assay measures an increase in intracellular calciumfollowing ligand-induced receptor activation. In the screen of CCR9antagonists, it was used as a secondary assay carried out on a FLIPR®machine (Molecular Devices, Mountain View, Calif.). To begin an assay,MOLT-4 cells were harvested by centrifugation of cell suspension, andresuspended to 1.5×10⁶ cells/mL in HBSS (with 1% fetal calf serum).Cells were then labeled with a calcium indicator dye Fluo-4 AM for 45minutes at 37° C. with gentle shaking. Following incubation, cells werepelletted, washed once with HBSS and resuspended in the same buffer at adensity of 1.6×10⁶ cells/mL. One hundred microliters of labeled cellswere mixed with 10 μL of test compound at the appropriate concentrationson an assay plate. Chemokine protein TECK was added at a finalconcentration of 25 nM to activate the receptor. The degree ofinhibition was determined by comparing calcium signals betweencompound-treated and untreated cells. IC50 calculations were furtherperformed by non-linear squares regression analysis using Graphpad Prism(Graphpad Software, San Diego, Calif.).

Discovery of CCR9 Antagonists

The discovery of CCR9 antagonists was carried out in two steps: First,RAM assay was used to screen a compound library in a high-throughputmanner. The assay detected compounds by their ability to cause apositive migration signal under RAM condition. Secondly, RAM positivecompounds were tested to determine their IC₅₀s using the conventionalmigration and calcium flux assays.

For instance, in a screen of approximately 100,000 compounds, 2000individual wells representing approximately 2% of total compounds showeda RAM index greater than 1.8. These compounds were cheery-picked andretested in duplicate wells by RAM assay. A total of 270 compounds, or0.27% of the library, were confirmed RAM positives.

Since a RAM positive signal indicates only the presence of a receptorantagonist and not how strongly it blocks receptor functions, the RAMpositive compounds were further tested for potency in calcium flux assayusing MOLT-4 cells. IC₅₀ determinations on this subset discoveredseveral compounds with IC₅₀'s less than 1 μM and that did not inhibitother chemokine receptors examined at significant levels.

In Vivo Efficacy Studies

The MDR1a-knockout mice, which lack the P-glycoprotein gene,spontaneously develop colitis under specific pathogen-free condition.The pathology in these animals has been characterized as Th1-type Tcell-mediated inflammation similar to ulcerative colitis in humans.Disease normally begins to develop at around 8-10 weeks after birth.However the ages at which disease emerges and the ultimate penetrancelevel often vary considerably among different animal facilities.

In a study using the MDR1a-knockout mice, the CCR9 antagonist shownbelow

was evaluated by prophylactic administration for its ability to delaydisease onset. Female mice (n=34) were dosed with 50 mg/kg twice a dayby subcutaneous injections for 14 consecutive weeks starting at age 10weeks. The study showed that the compound prevented IBD-associatedgrowth retardation. Moreover, the number of mice developing diarrhea wasalso lower among compound-treated mice (17%), compared to mice receivingvehicle alone (24%) (FIG. 1).

In the table below, structures and activity are provided forrepresentative compounds described herein. Activity is provided asfollows for either or both of the chemotaxis assay and/or calciummobilization assays, described above: +1000 nM<IC₅₀<10000 nM; ++, 100nM<IC₅₀<1000 nM; and +++, IC₅₀<100 nM.

TABLE 1 Compounds with activity in either or both of the chemotaxisassay and calcium mobilization assays, with IC₅₀ < 100 nM (+++)

TABLE 2 Compounds with activity in either or both of the chemotaxisassay and calcium mobilization assays, with 100 nM < IC₅₀ < 1000 nM (++)

TABLE 3 Compounds with activity in either or both of the chemotaxisassay and calcium mobilization assays, with 1000 nM < IC₅₀ < 10000 nM(+):

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference for allpurposes.

1-85. (canceled)
 86. A compound of formula (I) or a pharmaceuticallyacceptable salt thereof:

wherein X represents —OR₁; R₁ is selected from the group consisting ofhydrogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, aryl-C₁₋₄ alkyl,and aryloxy-C₁₋₄ alkyl; L is C(O); Z is 4-(1-oxy)pyridyl; and Y ishalogen.
 87. A composition comprising at least one compound or apharmaceutically acceptable salt thereof of claim
 86. 88. A method oftreating inflammatory bowel disease in a subject in need thereof,comprising administering to the subject an effective amount of acompound or a pharmaceutically acceptable salt thereof of claim
 86. 89.A compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein X represents —OR₁; R₁ is selected from the group consisting ofhydrogen, linear or branched C₁₋₆ haloalkyl, linear or branched C₁₋₆alkyl, C₃₋₆ cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, 5- to10-membered heteroaryl, aryl-C₁₋₄ alkyl, and aryloxy-C₁₋₄ alkyl; L isC(O); Z is 4-(1-oxy)pyridyl which is unsubstituted or substituted withunsubstituted C₁₋₈ alkyl; and Y is halogen.
 90. The compound of claim89, wherein Z is 4-(1-oxy)pyridyl which is unsubstituted or substitutedwith methyl.
 91. The compound of claim 90, wherein Z is 4-(1-oxy)pyridylwhich is substituted with methyl at the 2-position.
 92. The compound ofclaim 90, wherein Z is 4-(1-oxy)pyridyl which is unsubstituted.
 93. Thecompound of claim 92, wherein Y is chloro.
 94. The compound of claim 93,wherein Y is 4-chloro.
 95. The compound of claim 94, wherein X is parato the sulfonamide group.
 96. The compound of claim 95, wherein R₁ is alinear or branched C₁₋₆ haloalkyl or linear or branched C₁₋₆ alkyl. 97.The compound of claim 96, wherein R₁ is linear or branched C₁₋₆ alkyl.98. The compound of claim 97, wherein R₁ is a linear alkyl.
 99. Thecompound of claim 98, wherein R₁ is methyl or ethyl.
 100. The compoundof claim 97, wherein R₁ is branched alkyl.
 101. The compound of claim100, wherein R₁ is isopropyl.
 102. A composition comprising at least onecompound or a pharmaceutically acceptable salt thereof of claim
 89. 103.A method of treating inflammatory bowel disease in a subject in needthereof, comprising administering to the subject an effective amount ofa compound or a pharmaceutically acceptable salt thereof of claim 89.